TW201623295A - Dihydrothiazine and dihydrooxazine derivatives having BACE1 inhibitory activity - Google Patents

Dihydrothiazine and dihydrooxazine derivatives having BACE1 inhibitory activity Download PDF

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TW201623295A
TW201623295A TW104111465A TW104111465A TW201623295A TW 201623295 A TW201623295 A TW 201623295A TW 104111465 A TW104111465 A TW 104111465A TW 104111465 A TW104111465 A TW 104111465A TW 201623295 A TW201623295 A TW 201623295A
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日下部兼一
只野元太
駒野和雄
淵野光記
中原健二
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塩野義製藥股份有限公司
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Abstract

The present invention provides a compound which has an effect of inhibiting amyloid [beta] production, especially an effect of inhibiting BACE1, and which is useful as a therapeutic or prophylactic agent for diseases induced by production, secretion and/or deposition of amyloid [beta] proteins. A compound of the formula (I): wherein X is -S- or -O-, R<SP>3a</SP> is alkyl, haloalkyl or the like, R<SP>2a</SP> is H, halogen, alkyloxy, haloalkyloxy or the like, R<SP>2b</SP> is H or the like, R<SP>3b</SP> is H or alkyl, ring A and ring B is each independently a substituted or unsubstituted aromatic carbocycle, a substituted or unsubstituted aromatic heterocycle or the like, R1 is substituted or unsubstituted alkyl or the like, R5 is halogen or substituted or unsubstituted alkyl, and n is an integer of 0 to 2, or a pharmaceutically acceptable salt thereof.

Description

具有BACE1抑制活性之二氫噻 及二氫 衍生物Dihydrothiazide and dihydrogen derivatives having BACE1 inhibitory activity

本發明係關於具有澱粉狀蛋白β產生抑制活性且適用作治療或預防由澱粉狀蛋白β蛋白之產生、分泌及/或沈積所誘發之疾病之藥劑的化合物。 The present invention relates to a compound having amyloid β production inhibitory activity and being useful as an agent for treating or preventing a disease induced by the production, secretion and/or deposition of amyloid β protein.

在阿茲海默氏患者(Alzheimer's patient)之大腦中，廣泛觀測到由約40個胺基酸殘基組成之肽，稱作澱粉狀蛋白β蛋白，其在神經細胞外部積聚而形成不溶性斑點(老年斑)之。擔心此等老年斑殺死神經細胞而引起阿茲海默氏病，因此正在研究用於阿茲海默氏病之治療劑，諸如澱粉狀蛋白β蛋白之分解劑及澱粉狀蛋白疫苗。 In the brains of Alzheimer's patients, a peptide consisting of about 40 amino acid residues, called amyloid β protein, is widely observed to accumulate outside the nerve cells to form insoluble spots ( Age spots). Concerning that these senile plaques kill nerve cells and cause Alzheimer's disease, therapeutic agents for Alzheimer's disease such as amylin beta protein decomposing agent and amyloid vaccine are being studied.

分泌酶為一種酶，其使細胞中稱作澱粉狀蛋白β前驅蛋白(APP)之蛋白裂解且產生澱粉狀蛋白β蛋白。控制澱粉狀蛋白β蛋白之N末端之產生之酶稱作β-分泌酶(β位點APP裂解酶1，BACE1)。認為抑制此酶使得澱粉狀蛋白β蛋白之產生減少且將由於該抑制而產生用於阿茲海默氏病之治療劑或預防劑。 A secretase is an enzyme that cleaves a protein called amyloid [beta] precursor protein (APP) in a cell and produces amyloid [beta] protein. An enzyme that controls the production of the N-terminus of amyloid β protein is called β-secretase (β-site APP lyase 1, BACE1). It is believed that inhibition of this enzyme results in a decrease in the production of amyloid [beta] protein and will result in a therapeutic or prophylactic agent for Alzheimer's disease due to this inhibition.

專利文獻1至22及非專利文獻1揭示結構與本發明化合物類似之化合物。此等文獻中之每一者揭示各化合物適用作阿茲海默氏病、阿茲海默氏相關症狀、糖尿病或其類似者之治療劑，但實質上揭示之化合物中之每一者具有不同於本發明化合物之結構。 Patent Documents 1 to 22 and Non-Patent Document 1 disclose compounds having a structure similar to the compound of the present invention. Each of these documents discloses that each compound is suitable for use as a therapeutic agent for Alzheimer's disease, Alzheimer's related symptoms, diabetes or the like, but substantially each of the compounds disclosed is different The structure of the compound of the present invention.

[先前技術] [Prior technology] [專利文獻] [Patent Literature]

[專利文獻1]WO2007/049532 [Patent Document 1] WO2007/049532

[專利文獻2]WO2008/133273 [Patent Document 2] WO2008/133273

[專利文獻3]WO2008/133274 [Patent Document 3] WO2008/133274

[專利文獻4]WO2009/151098 [Patent Document 4] WO2009/151098

[專利文獻5]WO2010/047372 [Patent Document 5] WO2010/047372

[專利文獻6]WO2010/113848 [Patent Document 6] WO2010/113848

[專利文獻7]WO2011/071057 [Patent Document 7] WO2011/071057

[專利文獻8]WO2011/058763 [Patent Document 8] WO2011/058763

[專利文獻9]WO2011/070781 [Patent Document 9] WO2011/070781

[專利文獻10]WO2011/077726 [Patent Document 10] WO2011/077726

[專利文獻11]WO2011/071135 [Patent Document 11] WO2011/071135

[專利文獻12]WO2011/071109 [Patent Document 12] WO2011/071109

[專利文獻13]WO2012/057247 [Patent Document 13] WO2012/057247

[專利文獻14]WO2012/057248 [Patent Document 14] WO2012/057248

[專利文獻15]WO2012/147762 [Patent Document 15] WO2012/147762

[專利文獻16]WO2012/147763 [Patent Document 16] WO2012/147763

[專利文獻17]JP2012/250933A [Patent Document 17] JP2012/250933A

[專利文獻18]WO2014/010748 [Patent Document 18] WO2014/010748

[專利文獻19]JP2014/101354A [Patent Document 19] JP2014/101354A

[專利文獻20]WO2014/065434 [Patent Document 20] WO2014/065434

[專利文獻21]JP2014/101353A [Patent Document 21] JP2014/101353A

[專利文獻22]WO2013/110622 [Patent Document 22] WO2013/110622

[專利文獻23]WO2014/001228 [Patent Document 23] WO2014/001228

[專利文獻24]WO2013/041499 [Patent Document 24] WO2013/041499

[專利文獻25]WO2012/107371 [Patent Document 25] WO2012/107371

[專利文獻26]WO2011/069934 [Patent Document 26] WO2011/069934

[專利文獻27]WO2011/070029 [Patent Document 27] WO2011/070029

[專利文獻28]WO2012/139993 [Patent Document 28] WO2012/139993

[專利文獻29]WO2012/168164 [Patent Document 29] WO2012/168164

[專利文獻30]WO2012/168175 [Patent Document 30] WO2012/168175

[專利文獻31]WO2012/156284 [Patent Document 31] WO2012/156284

[專利文獻32]WO2014/166906 [Patent Document 32] WO2014/166906

[專利文獻33]WO2014/114532 [Patent Document 33] WO2014/114532

[專利文獻34]WO2013/027188 [Patent Document 34] WO2013/027188

[專利文獻35]WO2014/134341 [Patent Document 35] WO2014/134341

[專利文獻36]WO2008/103351 [Patent Document 36] WO2008/103351

[專利文獻37]US2008/0200445 [Patent Document 37] US2008/0200445

[專利文獻38]US2006/0287294 [Patent Document 38] US2006/0287294

[專利文獻39]WO2014/098831 [Patent Document 39] WO2014/098831

[非專利文獻] [Non-patent literature]

[非專利文獻1]Journal of Medicinal Chemistry,2013,56(10)，第3980-3995頁 [Non-Patent Document 1] Journal of Medicinal Chemistry, 2013, 56(10), pp. 3980-3995

本發明提供具有減少澱粉狀蛋白β蛋白產生之作用，尤其為BACE1抑制活性，且適用作治療由澱粉狀蛋白β蛋白之產生、分泌及/或沈積所誘發之疾病之藥劑的化合物。 The present invention provides a compound having an action of reducing the production of amyloid [beta] protein, particularly BACE1 inhibitory activity, and is useful as an agent for treating a disease induced by the production, secretion and/or deposition of amyloid [beta] protein.

本發明例如提供以下項中所述之發明。 The present invention provides, for example, the invention described in the following items.

(1)一種式(I)化合物， (1) a compound of formula (I),

其中X為-S-或-O-，(i)當X為-S-時，則R3a為烷基、鹵烷基、羥烷基或烷氧基烷基，R2a為鹵素、烷氧基或鹵烷氧基，且當R3a為鹵烷基時，R2a可為烷基，R2b為H，R2a及R2b連同其所連接之碳原子可形成經取代環烷，當R2a及R2b連同其所連接之碳原子可形成經取代環烷時，R3a可為H，(ii)當X為-O-時，則R3a為視情況經選自烷氧基及環烷基之一或多者取代之鹵烷基，或經選自鹵素之一或多者取代之環烷基，R2a為H、鹵素、烷基、烷氧基或鹵烷氧基，R2b為H，R2a及R2b連同其所連接之碳原子可形成經取代環烷，當R2a及R2b連同其所連接之碳原子可形成經取代環烷時，R3a可為H或烷基，R3b為H或烷基，[化學式2] Wherein X is -S- or -O-, (i) when X is -S-, then R 3a is alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl, and R 2a is halogen, alkoxy Or a haloalkoxy group, and when R 3a is a haloalkyl group, R 2a may be an alkyl group, R 2b is H, and R 2a and R 2b together with the carbon atom to which they are attached may form a substituted cycloalkane, when R When 2a and R 2b together with the carbon atom to which they are attached may form a substituted cycloalkane, R 3a may be H, (ii) when X is -O-, then R 3a is optionally selected from alkoxy and a ring. a haloalkyl group substituted by one or more alkyl groups, or a cycloalkyl group substituted by one or more halogens, R 2a is H, halogen, alkyl, alkoxy or haloalkoxy, R 2b H, R 2a and R 2b together with the carbon atom to which they are attached may form a substituted cycloalkane, and when R 2a and R 2b together with the carbon atom to which they are attached may form a substituted cycloalkane, R 3a may be H or an alkane Base, R 3b is H or alkyl, [Chemical Formula 2]

環A為經取代或未經取代之芳族碳環、經取代或未經取代之非芳族碳環、經取代或未經取代之芳族雜環或經取代或未經取代之非芳族雜環，環B為經取代或未經取代之芳族碳環、經取代或未經取代之非芳族碳環、經取代或未經取代之芳族雜環或經取代或未經取代之非芳族雜環，R1為經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基或經取代或未經取代之環烷基，R5為鹵素或經取代或未經取代之烷基，n為0至2之整數，其限制條件為排除以下化合物：(1)其中X為-O-、R3a為CH2F或CF3、R3b為H、R2a為H或F且R2b為H之化合物，(2)其中X為-O-、R3a為CHF2、R3b為H、R2a為OMe且R2b為H之化合物，(3)以下化合物： 或其醫藥學上可接受之鹽。 Ring A is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted non-aromatic group Heterocyclic ring, ring B is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted a non-aromatic heterocyclic ring, R 1 being a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group or a substituted or unsubstituted cycloalkyl group, R 5 is halogen or substituted or unsubstituted alkyl, and n is an integer of 0 to 2, with the proviso that the following compounds are excluded: (1) wherein X is -O-, and R 3a is CH 2 F or CF 3 , R 3b is H, R 2a is H or F and R 2b is H, (2) wherein X is -O-, R 3a is CHF 2 , R 3b is H, R 2a is OMe and R 2b is H Compound, (3) the following compounds: Or a pharmaceutically acceptable salt thereof.

(1-1)一種式(I)化合物，[化學式4] (1-1) a compound of the formula (I), [Chemical Formula 4]

其中X為-O-或-S-，(i)當X為-O-時，則R3a為鹵烷基，R2a為H、鹵素、烷基、烷氧基或鹵烷氧基，(ii)當X為-S-時，則R3a為烷基或鹵烷基，R2a為鹵素、烷氧基或鹵烷氧基，且當R3a為鹵烷基時，R2a可為烷基，R3b為H或烷基，及 Wherein X is -O- or -S-, (i) when X is -O-, then R 3a is haloalkyl, and R 2a is H, halogen, alkyl, alkoxy or haloalkoxy, Ii) when X is -S-, then R 3a is alkyl or haloalkyl, R 2a is halogen, alkoxy or haloalkoxy, and when R 3a is haloalkyl, R 2a may be alkane a base, R 3b is H or an alkyl group, and

環A為經取代或未經取代之芳族碳環、經取代或未經取代之非芳族碳環、經取代或未經取代之芳族雜環或經取代或未經取代之非芳族雜環，環B為經取代或未經取代之芳族碳環、經取代或未經取代之非芳族碳環、經取代或未經取代之芳族雜環或經取代或未經取代之非芳族雜環，R1為經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基或經取代或未經取代之環烷基，R5為鹵素或經取代或未經取代之烷基， n為0至2之整數，其限制條件為排除以下化合物：(1)其中X為-O-、R3a為CH2F或CF3、R3b為H且R2a為H或F之化合物，(2)以下化合物： Ring A is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted non-aromatic group Heterocyclic ring, ring B is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted a non-aromatic heterocyclic ring, R 1 being a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group or a substituted or unsubstituted cycloalkyl group, R 5 is halogen or substituted or unsubstituted alkyl, and n is an integer of 0 to 2, with the proviso that the following compounds are excluded: (1) wherein X is -O-, and R 3a is CH 2 F or CF 3 a compound wherein R 3b is H and R 2a is H or F, and (2) the following compounds:

或其醫藥學上可接受之鹽。 Or a pharmaceutically acceptable salt thereof.

(1-2)如第(1)項之化合物，其限制條件為排除以下化合物： (1-2) A compound according to item (1), which is restricted by excluding the following compounds:

(1)其中X為-O-、R3a為CH2F或CF3、R3b為H且R2a為H、F或OMe之化合物，(3)其中X為-O-、R3a為CHF2、R3b為H且R2a為OMe之化合物，或其醫藥學上可接受之鹽。 (1) A compound wherein X is -O-, R 3a is CH 2 F or CF 3 , R 3b is H and R 2a is H, F or OMe, (3) wherein X is -O- and R 3a is CHF 2. A compound wherein R 3b is H and R 2a is OMe, or a pharmaceutically acceptable salt thereof.

(2)如第(1)、(1-1)或(1-2)項之化合物，其中X為-O-，或其醫藥學上可接受之鹽。 (2) A compound according to the item (1), (1-1) or (1-2), wherein X is -O-, or a pharmaceutically acceptable salt thereof.

(3)如第(2)項之化合物，其中R3a為CH2F、CHF2、CF3、CH(F)CH3或CF2CH3，且R3b為H或CH3，或其醫藥學上可接受之鹽。 (3) A compound according to the item (2), wherein R 3a is CH 2 F, CHF 2 , CF 3 , CH(F)CH 3 or CF 2 CH 3 , and R 3b is H or CH 3 , or a pharmaceutical thereof A salt that is acceptable for learning.

(4)如第(2)項或第(3)項之化合物，其中R2a為H、F、CH3、OCH3或OCH2CF3，或其醫藥學上可接受之鹽。 (4) A compound according to the item (2) or (3), wherein R 2a is H, F, CH 3 , OCH 3 or OCH 2 CF 3 , or a pharmaceutically acceptable salt thereof.

(5)如第(2)項至第(4)項中任一項之化合物，其中R2a為H、鹵素或烷基，R2b為H，且R3a為CHF2、CH(F)CH3或CF2CH3，或其醫藥學上可接受之鹽。 (5) A compound according to any one of items (2) to (4), wherein R 2a is H, halogen or alkyl, R 2b is H, and R 3a is CHF 2 , CH(F)CH 3 or CF 2 CH 3 , or a pharmaceutically acceptable salt thereof.

(5-1)如第(2)項至第(4)項中任一項之化合物，其中R2a為H或鹵 素，且R3a為CHF2、CH(F)CH3或CF2CH3，或其醫藥學上可接受之鹽。 (5-1) A compound according to any one of items (2) to (4), wherein R 2a is H or halogen, and R 3a is CHF 2 , CH(F)CH 3 or CF 2 CH 3 , or a pharmaceutically acceptable salt thereof.

(6)如第(2)項至第(4)項中任一項之化合物，其中R2a為H或鹵素，R2b為H，R3a為CH2F或CF3，R3b為烷基，且R1為未經取代烷基，或其醫藥學上可接受之鹽。 (6) A compound according to any one of items (2) to (4), wherein R 2a is H or halogen, R 2b is H, R 3a is CH 2 F or CF 3 , and R 3b is alkyl And R 1 is an unsubstituted alkyl group, or a pharmaceutically acceptable salt thereof.

(6-1)如第(2)項至第(4)項中任一項之化合物，其中R2a為H或鹵素，R3a為CH2F或CF3，且R3b為烷基，或其醫藥學上可接受之鹽。 (6) The compound of any one of (2) to (4), wherein R 2a is H or halogen, R 3a is CH 2 F or CF 3 , and R 3b is alkyl, or Its pharmaceutically acceptable salt.

(7)如第(2)項至第(4)項中任一項之化合物，其中R2a為烷基、烷氧基或鹵烷氧基，或其醫藥學上可接受之鹽。 (7) The item (2) to compound (4) according to any one of the items, wherein R 2a is acceptable on an alkyl, alkoxy or haloalkoxy, or a pharmaceutically acceptable salt thereof.

(8)如第(2)項至第(4)項中任一項之化合物，其中 (8) A compound according to any one of items (2) to (4), wherein

R5為鹵素且n為1或2，或其醫藥學上可接受之鹽。 R 5 is a halogen and n is 1 or 2, or a pharmaceutically acceptable salt thereof.

(9)如第(2)項至第(4)項中任一項之化合物，其中R3a為經烷氧基或環烷基取代之鹵烷基，或其醫藥學上可接受之鹽。 The compound according to any one of the items (2) to (4), wherein R 3a is a haloalkyl group substituted by an alkoxy group or a cycloalkyl group, or a pharmaceutically acceptable salt thereof.

(10)如第(1)項、第(1-1)項及第(1-2)項中任一項之化合物，其中X為-S-，R2a為鹵素或烷氧基，R2b為H，R3a為烷基、鹵烷基、羥烷基或烷氧基烷基，且R3b為H，或其醫藥學上可接受之鹽。 (10) A compound according to any one of (1), wherein the X is -S-, R 2a is halogen or alkoxy, R 2b Is H, R 3a is alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl, and R 3b is H, or a pharmaceutically acceptable salt thereof.

(11)如第(1)項之化合物，其中X為-S-，R2a為F，R2b為H，R3a為CH3或CH2F，且R3b為H，或其醫藥學上可接受之鹽。 (11) A compound according to the item (1), wherein X is -S-, R 2a is F, R 2b is H, R 3a is CH 3 or CH 2 F, and R 3b is H, or a pharmaceutically thereof thereof Acceptable salt.

(12)如第(1)項、第(1-1)項及第(1-2)項中任一項之化合物，其中R2a及R2b連同其所連接之碳原子形成經鹵素取代之環烷，R3a為H或烷基，或其醫藥學上可接受之鹽。 (12) A compound according to any one of the preceding claims, wherein R 2a and R 2b together with the carbon atom to which they are attached form a halogen-substituted A cycloalkane, R 3a is H or an alkyl group, or a pharmaceutically acceptable salt thereof.

(13)如第(1)項、第(1-1)項、第(1-2)項、第(2)至(5)項、第(5-1)項、第(6)項、第(6-1)項及第(7)至(12)項中任一項之化合物，其中R1 為烷基，或其醫藥學上可接受之鹽。 (13) Items (1), (1-1), (1-2), (2) to (5), (5-1), (6), The compound of any one of (7) to (12), wherein R 1 is an alkyl group, or a pharmaceutically acceptable salt thereof.

(14)如第(1)項、第(1-1)項、第(1-2)項、第(2)(5)項、第(5-1)項、第(6)項、第(6-1)項及第(7)至(13)項中任一項之化合物，其中環A為 (14) As in items (1), (1-1), (1-2), (2) (5), (5-1), (6), (6-1) The compound of any one of (7) to (13), wherein ring A is

其中R4為H或鹵素，且-Z=為-CH=或-N=，或其醫藥學上可接受之鹽。 Wherein R 4 is H or halogen, and -Z = is -CH= or -N=, or a pharmaceutically acceptable salt thereof.

(15)如第(14)項之化合物，其中R4為鹵素且-Z=為-CH=，或其醫藥學上可接受之鹽。 (15) A compound according to the item (14), wherein R 4 is halogen and -Z = is -CH=, or a pharmaceutically acceptable salt thereof.

(16)如第(1)項、第(1-1)項、第(1-2)項、第(2)至(5)項、第(5-1)項、第(6)項、第(6-1)項及第(7)至(15)至(15)項中任一項之化合物，其中環B為經取代或未經取代之吡啶、經取代或未經取代之吡、經取代或未經取代之嘧啶、經取代或未經取代之噠或經取代或未經取代之唑，或其醫藥學上可接受之鹽。 (16) Items (1), (1-1), (1-2), (2) to (5), (5-1), (6), The compound of any one of (6) and (7) to (15) to (15), wherein the ring B is a substituted or unsubstituted pyridine, a substituted or unsubstituted pyridyl Substituted or unsubstituted pyrimidine, substituted or unsubstituted hydrazine Or substituted or unsubstituted An azole, or a pharmaceutically acceptable salt thereof.

(16-1)如第(1)項、第(1-1)項、第(1-2)項、第(2)至(5)項、第(5-1)項、第(6)項、第(6-1)項及第(7)至(15)項中任一項之化合物，其中環B為經取代或未經取代之吡啶、經取代或未經取代之吡或經取代或未經取代之唑，或其醫藥學上可接受之鹽。 (16-1) For items (1), (1-1), (1-2), (2) to (5), (5-1), (6) The compound of any one of (6) to (15), wherein the ring B is a substituted or unsubstituted pyridine, a substituted or unsubstituted pyridyl Or substituted or unsubstituted An azole, or a pharmaceutically acceptable salt thereof.

(17)一種醫藥組合物，其包含如第(1)項、第(1-1)項、第(1-2)項、第(2)至(5)項、第(5-1)項、第(6)項、第(6-1)項、第(7)至(16)項及第(16-1)項中任一項之化合物，或其醫藥學上可接受之鹽。 (17) A pharmaceutical composition comprising the items (1), (1-1), (1-2), (2) to (5), and (5-1) And a compound of any one of (6), (6), (7) to (16), and (16-1), or a pharmaceutically acceptable salt thereof.

(18)一種具有BACE1抑制活性之醫藥組合物，其包含如第(1)項、第(1-1)項、第(1-2)項、第(2)至(5)項、第(5-1)項、第(6)項、第(6-1)項、第(7)至(16)項及第(16-1)項中任一項之化合物，或其醫藥學上 可接受之鹽。 (18) A pharmaceutical composition having BACE1 inhibitory activity, comprising the items (1), (1-1), (1-2), (2) to (5), ( a compound of any one of 5-1), (6), (6-1), (7) to (16) and (16-1), or a pharmaceutical thereof Acceptable salt.

(19)一種抑制BACE1活性之方法，其包含投與如第(1)項、第(1-1)項、第(1-2)項、第(2)至(5)項、第(5-1)項、第(6)項、第(6-1)項、第(7)至(16)項及第(16-1)項中任一項之化合物，或其醫藥學上可接受之鹽。 (19) A method for inhibiting BACE1 activity, comprising administering, as in item (1), item (1-1), item (1-2), item (2) to (5), (5) a compound of any one of -1), (6), (6-1), (7) to (16) and (16-1), or a pharmaceutically acceptable compound thereof Salt.

(20)如第(1)項、第(1-1)項、第(1-2)項、第(2)至(5)項、第(5-1)項、第(6)項、第(6-1)項、第(7)至(16)項及第(16-1)項中任一項之化合物，或其醫藥學上可接受之鹽，其用於抑制BACE1活性之方法中。 (20) Items (1), (1-1), (1-2), (2) to (5), (5-1), (6), The compound of any one of (6), (7), (16), or (16-1), or a pharmaceutically acceptable salt thereof, for inhibiting BACE1 activity in.

(21)如第(17)項或第(18)項之醫藥組合物，其用於治療或預防阿茲海默癡呆症、輕度認知障礙或前驅性阿茲海默氏病(Alzheimer's disease)、用於預防阿茲海默癡呆症、輕度認知障礙或前驅性阿茲海默氏病之進展或用於預防存在阿茲海默癡呆症風險之無症狀患者中之進展。 (21) A pharmaceutical composition according to item (17) or (18) for use in the treatment or prevention of Alzheimer's dementia, mild cognitive impairment or prodromal Alzheimer's disease It is used to prevent progression of Alzheimer's dementia, mild cognitive impairment or prodromal Alzheimer's disease or to prevent progression in asymptomatic patients at risk for Alzheimer's dementia.

(22)一種治療或預防阿茲海默癡呆症、輕度認知障礙或前驅性阿茲海默氏病、用於預防阿茲海默癡呆症、輕度認知障礙或前驅性阿茲海默氏病之進展或用於預防存在阿茲海默癡呆症風險之無症狀患者中之進展之方法，其包含投與如第(1)項、第(1-1)項、第(1-2)項、第(2)至(5)項、第(5-1)項、第(6)項、第(6-1)項、第(7)至(16)項及第(16-1)項中任一項之化合物，或其醫藥學上可接受之鹽。 (22) A treatment or prevention of Alzheimer's dementia, mild cognitive impairment or prodromal Alzheimer's disease, prevention of Alzheimer's dementia, mild cognitive impairment or prodromal Alzheimer's disease The progress of the disease or the method for preventing progression in asymptomatic patients at risk of Alzheimer's dementia, including the administration of items (1), (1-1), (1-2) Items, items (2) to (5), (5-1), (6), (6-1), (7) to (16) and (16-1) A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

(23)一種如第(1)項、第(1-1)項、第(1-2)項、第(2)至(5)項、第(5-1)項、第(6)項、第(6-1)項、第(7)至(16)項及第(16-1)項中任一項之化合物，或其醫藥學上可接受之鹽，其用於治療或預防阿茲海默癡呆症、輕度認知障礙或前驅性阿茲海默氏病、用於預防阿茲海默癡呆症、輕度認知障礙或前驅性阿茲海默氏病之進展或用於預防存在阿茲海默癡呆症風險之無症狀患者中之進展。 (23) A sub-paragraph (1), (1-1), (1-2), (2) to (5), (5-1), (6) The compound of any one of (6), (7) to (16) and (16-1), or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention thereof Alzheimer's disease, mild cognitive impairment or prodromal Alzheimer's disease, prevention of Alzheimer's dementia, mild cognitive impairment or progression of prodromal Alzheimer's disease or for prevention of presence Progress in asymptomatic patients at risk of Alzheimer's dementia.

(24)一種如第(1)項、第(1-1)項、第(1-2)項、第(2)至(5)項、第 (5-1)項、第(6)項、第(6-1)項、第(7)至(16)項及第(16-1)項中任一項之化合物或其醫藥學上可接受之鹽之用途，其用於製造抑制BACE1活性之藥物。 (24) A sub-paragraph (1), (1-1), (1-2), (2) to (5), a compound of any one of (5-1), (6), (6-1), (7) to (16) and (16-1) or a pharmaceutically acceptable compound thereof The use of the accepted salt for the manufacture of a medicament for inhibiting BACE1 activity.

(25)如第(17)項或第(18)項之醫藥組合物，其用於治療或預防由澱粉狀蛋白β蛋白之產生、分泌或沈積誘發之疾病。 (25) A pharmaceutical composition according to item (17) or (18), which is for use in the treatment or prevention of a disease induced by the production, secretion or deposition of amyloid [beta] protein.

(26)一種治療或預防由澱粉狀蛋白β蛋白之產生、分泌或沈積誘發之疾病之方法，其包含投與如第(1)項、第(1-1)項、第(1-2)項、第(2)至(5)項、第(5-1)項、第(6)項、第(6-1)項、第(7)至(16)項及第(16-1)項中任一項之化合物或其醫藥學上可接受之鹽。 (26) A method for treating or preventing a disease induced by production, secretion or deposition of amyloid [beta] protein, comprising administering as in item (1), item (1-1), (1-2) Items, items (2) to (5), (5-1), (6), (6-1), (7) to (16) and (16-1) A compound according to any one of the invention, or a pharmaceutically acceptable salt thereof.

(27)一種如第(1)項、第(1-1)項、第(1-2)項、第(2)至(5)項、第(5-1)項、第(6)項、第(6-1)項、第(7)至(16)項及第(16-1)項中任一項之化合物或其醫藥學上可接受之鹽，其用於治療或預防由澱粉狀蛋白β蛋白之產生、分泌或沈積誘發之疾病。 (27) A sub-paragraph (1), (1-1), (1-2), (2) to (5), (5-1), (6) The compound of any one of (6), (7), (16), or (16-1), or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of starch A disease induced by the production, secretion or deposition of a protein β protein.

(28)一種如第(1)項、第(1-1)項、第(1-2)項、第(2)至(5)項、第(5-1)項、第(6)項、第(6-1)項、第(7)至(16)項及第(16-1)項中任一項之化合物或其醫藥學上可接受之鹽之用途，其用於製造治療或預防由澱粉狀蛋白β蛋白之產生、分泌或沈積誘發之疾病之藥物。 (28) A sub-paragraph (1), (1-1), (1-2), (2) to (5), (5-1), (6) The use of a compound of any one of (6), (7), (16), and (16-1), or a pharmaceutically acceptable salt thereof, for the manufacture of a treatment or A drug for preventing a disease caused by the production, secretion or deposition of amyloid β protein.

(29)如第(17)項或第(18)項之醫藥組合物，其用於治療或預防阿茲海默癡呆症。 (29) A pharmaceutical composition according to item (17) or (18) for use in the treatment or prevention of Alzheimer's dementia.

(30)一種治療或預防阿茲海默癡呆症之方法，其包含投與如第(1)項、第(1-1)項、第(1-2)項、第(2)至(5)項、第(5-1)項、第(6)項、第(6-1)項、第(7)至(16)項及第(16-1)項中任一項之化合物，或其醫藥學上可接受之鹽。 (30) A method for treating or preventing Alzheimer's dementia comprising administering items (1), (1-1), (1-2), (2) to (5) a compound of any one of (5), (6), (6), (7) to (16) and (16-1), or Its pharmaceutically acceptable salt.

(31)一種如第(1)項、第(1-1)項、第(1-2)項、第(2)至(5)項、第(5-1)項、第(6)項、第(6-1)項、第(7)至(16)項及第(16-1)項中任一項之化合物，或其醫藥學上可接受之鹽，其用於治療或預防阿茲海默癡呆 症。 (31) A sub-paragraph (1), (1-1), (1-2), (2) to (5), (5-1), (6) The compound of any one of (6), (7) to (16) and (16-1), or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention thereof Zimmermer dementia disease.

(32)一種如第(1)項、第(1-1)項、第(1-2)項、第(2)至(5)項、第(5-1)項、第(6)項、第(6-1)項、第(7)至(16)項及第(16-1)項中任一項之化合物，或其醫藥學上可接受之鹽之用途，其用於製造治療或預防阿茲海默癡呆症之藥物。 (32) A sub-paragraph (1), (1-1), (1-2), (2) to (5), (5-1), (6) The use of a compound according to any one of the items (6-1), (7) to (16) and (16-1), or a pharmaceutically acceptable salt thereof, for the manufacture of a treatment Or drugs that prevent Alzheimer's dementia.

本發明化合物具有BACE1抑制活性且適用作用於治療及/或預防由澱粉狀蛋白β蛋白之產生、分泌或沈積誘發之疾病，如阿茲海默癡呆症之藥劑。 The compound of the present invention has BACE1 inhibitory activity and is suitable for use in the treatment and/or prevention of diseases caused by the production, secretion or deposition of amyloid β protein, such as Alzheimer's dementia.

(33)一種醫藥組合物，其包含如第(1)項、第(1-1)項、第(1-2)項、第(2)至(5)項、第(5-1)項、第(6)項、第(6-1)項、第(7)至(16)項及第(16-1)項中任一項之化合物，或其醫藥學上可接受之鹽，用於經口投與。 (33) A pharmaceutical composition comprising the items (1), (1-1), (1-2), (2) to (5), and (5-1) And a compound of any one of (6), (6), (7) to (16) and (16-1), or a pharmaceutically acceptable salt thereof, for use It is administered by mouth.

(34)如(33)之醫藥組合物，其為錠劑、散劑、顆粒劑、膠囊、丸劑、膜、懸浮液、乳液、酏劑、糖漿、檸檬劑、醑劑、芳族水、萃取液、煎劑或酊劑。 (34) The pharmaceutical composition according to (33), which is a tablet, a powder, a granule, a capsule, a pill, a film, a suspension, an emulsion, an elixir, a syrup, a lemon, a tincture, an aromatic water, an extract , decoction or tincture.

(35)如(34)之醫藥組合物，其為糖包衣錠、薄膜包衣錠、腸溶衣錠、緩釋錠、糖衣錠、舌下錠、頰內錠、咀嚼錠、口腔崩解錠、乾糖漿、軟膠囊、微膠囊或緩釋膠囊。 (35) The pharmaceutical composition according to (34), which is a sugar-coated tablet, a film-coated tablet, an enteric coated tablet, a sustained-release tablet, a sugar-coated tablet, a sublingual tablet, a buccal ingot, a chewable tablet, an orally disintegrating tablet. , dry syrup, soft capsules, microcapsules or sustained release capsules.

(36)一種醫藥組合物，其包含如第(1)項、第(1-1)項、第(1-2)項、第(2)至(5)項、第(5-1)項、第(6)項、第(6-1)項、第(7)至(16)項及第(16-1)項中任一項之化合物，或其醫藥學上可接受之鹽，用於非經腸投與。 (36) A pharmaceutical composition comprising the items (1), (1-1), (1-2), (2) to (5), and (5-1) And a compound of any one of (6), (6), (7) to (16) and (16-1), or a pharmaceutically acceptable salt thereof, for use It is administered parenterally.

(37)如(36)之醫藥組合物，其用於經皮、皮下、靜脈內、動脈內、肌肉內、腹膜內、經黏膜、吸入、經鼻、經眼、耳內或經***投與。 (37) A pharmaceutical composition according to (36) for percutaneous, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, transocular, intraocular or vaginal administration .

(38)如(36)或(37)之醫藥組合物，其為注射劑、輸注液、滴眼劑、滴鼻劑、滴耳劑、氣溶膠、吸入劑、洗劑、浸膠、搽劑、漱口劑、灌腸劑、軟膏、硬膏劑、膠凍、乳膏劑、貼片、熱罨劑、外部粉末或栓劑。 (38) The pharmaceutical composition according to (36) or (37), which is an injection, an infusion solution, an eye drop, a nasal drop, an ear drop, an aerosol, an inhalant, a lotion, a dipping agent, an expectorant, Mouthwash, enemas, ointments, plasters, jellies, creams, patches, chelating agents, external powders or suppositories.

(39)一種醫藥組合物，其包含如第(1)項、第(1-1)項、第(1-2)項、第(2)至(5)項、第(5-1)項、第(6)項、第(6-1)項、第(7)至(16)項及第(16-1)項中任一項之化合物，或其醫藥學上可接受之鹽，用於小兒或老年患者。 (39) A pharmaceutical composition comprising items (1), (1-1), (1-2), (2) to (5), and (5-1) And a compound of any one of (6), (6), (7) to (16) and (16-1), or a pharmaceutically acceptable salt thereof, for use In children or elderly patients.

(40)一種醫藥組合物，其由如第(1)項、第(1-1)項、第(1-2)項、第(2)至(5)項、第(5-1)項、第(6)項、第(6-1)項、第(7)至(16)項及第(16-1)項中任一項之化合物，或其醫藥學上可接受之鹽及乙醯膽鹼酯酶抑制劑、NMDA拮抗劑或其他用於阿茲海默癡呆症之藥物之組合組成。 (40) A pharmaceutical composition comprising, for example, item (1), item (1-1), item (1-2), item (2) to (5), item (5-1) , a compound of any one of (6), (6), (7) to (16) and (16-1), or a pharmaceutically acceptable salt thereof and A combination of a cholinesterase inhibitor, an NMDA antagonist, or other drug for Alzheimer's dementia.

(41)一種醫藥組合物，其包含如第(1)項、第(1-1)項、第(1-2)項、第(2)至(5)項、第(5-1)項、第(6)項、第(6-1)項、第(7)至(16)項及第(16-1)項中任一項之化合物，或其醫藥學上可接受之鹽，用於與乙醯膽鹼酯酶抑制劑、NMDA拮抗劑或其他用於阿茲海默癡呆症之藥物之組合療法。 (41) A pharmaceutical composition comprising the items (1), (1-1), (1-2), (2) to (5), and (5-1) And a compound of any one of (6), (6), (7) to (16) and (16-1), or a pharmaceutically acceptable salt thereof, for use Combination therapy with an acetylcholinesterase inhibitor, an NMDA antagonist or other drug for Alzheimer's dementia.

本文中所用之術語之各自的含義描述於下文中。除非另外說明，否則在單獨及組合使用時，各術語以相同含義使用。 The respective meanings of the terms used herein are described below. Unless otherwise stated, the terms are used in the same meaning when used individually and in combination.

在本說明書中，術語「由組成」意謂僅具有組分。 In the present specification, the term "consisting of" means having only components.

在本說明書中，術語「包含」意謂不限於組分且不排除未描述因素。 In the present specification, the term "comprising" means not limited to components and does not exclude undescribed factors.

在本說明書中，「鹵素」包括氟、氯、溴及碘。氟及氯為較佳的。 In the present specification, "halogen" includes fluorine, chlorine, bromine and iodine. Fluorine and chlorine are preferred.

在本說明書中，「烷基」包括1至15之碳數，例如1至10之碳數，例如1至6之碳數及例如1至4之碳數之直鏈或分支鏈烷基。實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基、正戊基、異戊基、新戊基、己基、異己基、正庚基、異庚基、正辛基、異辛基、正壬基及正癸基。實例為甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基及正戊基。 In the present specification, "alkyl" includes a carbon number of 1 to 15, for example, a carbon number of 1 to 10, for example, a carbon number of 1 to 6 and a linear or branched alkyl group of, for example, 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl , n-heptyl, isoheptyl, n-octyl, isooctyl, n-decyl and n-decyl. Examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tert-butyl and n-pentyl.

在一個實施例中，「烷基」為甲基、乙基、正丙基、異丙基或第三丁基。 In one embodiment, "alkyl" is methyl, ethyl, n-propyl, isopropyl or tert-butyl.

術語「烯基」包括在任何可用位置具有一或多個雙鍵之2至15之碳數，例如2至10之碳數，例如2至6之碳數及例如2至4之碳數之直鏈或分支鏈烯基。實例包括乙烯基、烯丙基、丙烯基、異丙烯基、丁烯基、異丁烯基、戊烯基、丁二烯基、戊烯基、異戊烯基、戊二烯基、己烯基、異己烯基、己二烯基、庚烯基、辛烯基、壬烯基、癸烯基、十一烯基、十二烯基、十三烯基、十四烯基及十五烯基。實例為乙烯基、烯丙基、丙烯基、異丙烯基及丁烯基。 The term "alkenyl" includes a carbon number of from 2 to 15 having one or more double bonds at any available position, for example a carbon number of from 2 to 10, such as from 2 to 6 carbon atoms and, for example, from 2 to 4 carbon atoms. Chain or branched alkenyl. Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, Isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl and pentadecenyl. Examples are vinyl, allyl, propenyl, isopropenyl and butenyl.

術語「炔基」包括在視情況選用之位置具有一或多個參鍵之2至15之碳數，例如2至10之碳數，例如2至8之碳數，例如2至6之碳數及例如2至4之碳數之直鏈或分支鏈炔基。特定實例為乙炔基、丙炔基、丁炔基、戊炔基、己炔基、庚炔基、辛炔基、壬炔基及癸炔基。此等基團可在任何可用位置具有另一雙鍵。實例為乙炔基、丙炔基、丁炔基及戊炔基。 The term "alkynyl" includes the number of carbons of 2 to 15 having one or more of the referenced positions, as the case may be, for example, a carbon number of 2 to 10, such as a carbon number of 2 to 8, such as a carbon number of 2 to 6. And a linear or branched alkynyl group having, for example, a carbon number of 2 to 4. Specific examples are ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, decynyl and decynyl. These groups may have another double bond at any available position. Examples are ethynyl, propynyl, butynyl and pentynyl.

術語「伸烷基」包括1至15之碳數，例如1至10之碳數，例如1至6之碳數及例如1至4之碳數之直鏈或分支鏈二價碳鏈。實例為亞甲基、伸乙基、伸丙基、伸丁基、伸戊基及伸己基。 The term "alkylene" includes carbon numbers of from 1 to 15, such as from 1 to 10 carbon atoms, such as from 1 to 6 carbon atoms and straight or branched chain divalent carbon chains such as from 1 to 4 carbon atoms. Examples are methylene, ethyl, propyl, butyl, pentyl and hexyl.

「伸烷二氧基」中之伸烷基部分與以上「伸烷基」相同。實例為亞甲二氧基及伸乙二氧基。 The alkylene moiety in "alkylenedioxy" is the same as the above "alkylene". Examples are methylenedioxy and ethylenedioxy.

術語「芳族碳環基」包括為單環且由兩個或兩個以上環組成之芳族烴基。實例為6至14之碳數之芳族烴基，且特定實例為苯基、萘基、蒽基及菲基。 The term "aromatic carbocyclic group" includes an aromatic hydrocarbon group which is monocyclic and composed of two or more rings. Examples are aromatic hydrocarbon groups having a carbon number of 6 to 14, and specific examples are phenyl, naphthyl, anthryl and phenanthryl.

在一個實施例中，「芳族碳環基」為苯基。 In one embodiment, the "aromatic carbocyclic group" is a phenyl group.

術語「非芳族碳環基」包括為單環或由兩個或兩個以上環組成之飽和碳環基或不飽和非芳族碳環基。兩個或兩個以上環之「非芳族碳環基」包括稠合環基，其中非芳族單環碳環或兩個或兩個以上環之非芳族碳環與以上「芳族碳環基」之環稠合。 The term "non-aromatic carbocyclic group" includes a saturated carbocyclic group or an unsaturated non-aromatic carbocyclic group which is a single ring or consists of two or more rings. "Non-aromatic carbocyclic groups" of two or more rings include fused ring groups in which a non-aromatic monocyclic carbocyclic ring or a non-aromatic carbocyclic ring of two or more rings and the above "aromatic carbon" The ring of the ring is fused.

另外，「非芳族碳環基」亦包括具有橋鍵或環基以形成如下螺環之環基： Further, the "non-aromatic carbocyclic group" also includes a ring group having a bridge or a ring group to form a spiro ring as follows:

術語「非芳族單環碳環」包括具有3至16個碳原子，例如3至12個碳原子，例如3至8個碳原子及例如3至5個碳原子之基團。實例為環丙烷、環丁烷、環戊烷、環己烷、環庚烷、環辛烷、環壬烷、環癸烷、環丙烯、環丁烯、環戊烯、環己烯、環庚烯及環己二烯。 The term "non-aromatic monocyclic carbocycle" includes groups having from 3 to 16 carbon atoms, for example from 3 to 12 carbon atoms, for example from 3 to 8 carbon atoms and, for example, from 3 to 5 carbon atoms. Examples are cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclodecane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptane Alkene and cyclohexadiene.

由兩個或兩個以上環組成之非芳族碳環基之實例包括具有6至14個碳原子之基團，且實例為茚滿基、茚基、苊基、四氫萘基及茀基。 Examples of the non-aromatic carbocyclic group consisting of two or more rings include a group having 6 to 14 carbon atoms, and examples are indanyl, indenyl, fluorenyl, tetrahydronaphthyl and anthracenyl. .

術語「環烷基」包括3至10之碳數，例如3至8之碳數及例如4至8之碳數之碳環基。實例為環丙基、環丁基、環戊基、環己基、環庚基、環辛基、環壬基及環癸基。 The term "cycloalkyl" includes a carbon number of from 3 to 10, such as a carbon number of from 3 to 8, and a carbocyclic group such as a carbon number of from 4 to 8. Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclodecyl.

術語「環烷」包括3至10之碳數，例如3至8之碳數，例如3至5之 碳數之碳環。實例為環丙烷、環丁烷、環戊烷、環己烷、環庚烷、環辛烷、環壬烷及環癸烷。 The term "cycloalkane" includes a carbon number of 3 to 10, such as a carbon number of 3 to 8, such as 3 to 5 Carbon ring of carbon number. Examples are cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclodecane and cyclodecane.

「環烷基烷基」、「環烷基胺基」及「環烷基烷氧基」中之環烷基部分與以上「環烷」相同。 The cycloalkyl moiety in "cycloalkylalkyl", "cycloalkylamino" and "cycloalkylalkoxy" is the same as the above "cycloalkane".

術語「芳族雜環基」包括為單環或由兩個或兩個以上環組成之芳族基，其含有一或多個獨立地選自氧、硫及氮原子之雜原子。 The term "aromatic heterocyclic group" includes an aromatic group consisting of a single ring or consisting of two or more rings containing one or more hetero atoms independently selected from oxygen, sulfur and nitrogen atoms.

兩個或兩個以上環之「芳族雜環基」包括稠合環基，其中芳族單環雜環基或由兩個或兩個以上環組成之非芳族雜環基與以上「芳族碳環基」之環稠合。 The "aromatic heterocyclic group" of two or more rings includes a fused ring group in which an aromatic monocyclic heterocyclic group or a non-aromatic heterocyclic group consisting of two or more rings and the above "aryl" The ring of the family carbocyclic group is fused.

術語「芳族單環雜環基」包括5至8員基團，且例如為5至6員基團。實例為吡咯基、咪唑基、吡唑基、吡啶基、噠基、嘧啶基、吡基、***基、三基、四唑基、呋喃基、噻吩基、異唑基、唑基、二唑基、異噻唑基、噻唑基及噻二唑基。 The term "aromatic monocyclic heterocyclic group" includes a 5 to 8 member group and is, for example, a 5 to 6 member group. Examples are pyrrolyl, imidazolyl, pyrazolyl, pyridyl, fluorene Base, pyrimidinyl, pyridyl Base, triazolyl, three Base, tetrazolyl, furyl, thienyl, iso Azolyl, Azolyl, Diazolyl, isothiazolyl, thiazolyl and thiadiazolyl.

芳族雙環雜環基之實例包括9至10員基團，且實例為吲哚啉基、異吲哚啉基、吲唑啉基、吲哚基、喹啉基、異喹啉基、啉基、酞基、喹唑啉基、啶基、喹喏啉基、嘌呤基、喋啶基、苯并咪唑基、苯并異唑基、苯并唑基、苯并二唑基、苯并異噻唑基、苯并噻唑基、苯并噻二唑基、苯并呋喃基、異苯并呋喃基、苯并噻吩基、苯并***基、咪唑并吡啶基、***并吡啶基、咪唑并噻唑基、吡并噠基、唑并吡啶基及噻唑并吡啶基。 Examples of the aromatic bicyclic heterocyclic group include a 9 to 10 member group, and examples are a porphyrin group, an isoindolyl group, an oxazoline group, and an anthracene. Base, quinolyl, isoquinolyl, Olinyl group, hydrazine Base, quinazolinyl, Pyridyl, quinoxalinyl, fluorenyl, acridinyl, benzimidazolyl, benziso Azolyl, benzo Azolyl, benzo Diazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzotriazolyl, imidazopyridyl, three Zoled pyridyl, imidazothiazolyl, pyridyl And base, Zoxalopyridyl and thiazolopyridyl.

三個或三個以上環之芳族雜環基之實例包括13至14員基團，且實例為咔唑基、吖啶基、基、啡噻基、啡噻基、啡基及二苯并呋喃基。 Examples of the aromatic heterocyclic group of three or more rings include a 13 to 14 member group, and examples are a carbazolyl group, an acridinyl group, Thiophene Base Thioyl, brown And dibenzofuranyl.

術語「非芳族雜環基」包括為單環或由兩個或兩個以上環組成之非芳族基，其含有一或多個獨立地選自氧、硫及氮原子之雜原子。 The term "non-aromatic heterocyclic group" includes a non-aromatic group consisting of a single ring or consisting of two or more rings containing one or more heteroatoms independently selected from oxygen, sulfur and nitrogen atoms.

兩個或兩個以上環之「非芳族雜環基」包括稠合環基，其中非 芳族單環雜環基或兩個或兩個以上環之非芳族雜環基與以上「芳族碳環基」、「非芳族碳環基」及/或「芳族雜環基」之環稠合。 "non-aromatic heterocyclic group" of two or more rings includes a fused ring group, wherein An aromatic monocyclic heterocyclic group or a non-aromatic heterocyclic group of two or more rings and the above "aromatic carbocyclic group", "non-aromatic carbocyclic group" and/or "aromatic heterocyclic group" The ring is fused.

另外，「非芳族雜環基」亦包括具有橋鍵或環基以形成如下螺環之環基： Further, the "non-aromatic heterocyclic group" also includes a ring group having a bridge or a ring group to form a spiro ring as follows:

術語「非芳族單環雜環基」包括3至8員環，且例如為4員、5員或6員環。實例為二氧雜環己烷基、硫雜環丙烷基、環氧乙烷基、氧雜環丁基、氧雜硫基、氮雜環丁基、噻烷基、噻唑啶基、吡咯啶基、吡咯啉基、咪唑啶基、咪唑啉基、吡唑啶基、吡唑啉基、哌啶基、哌基、嗎啉基、N-嗎啉基、硫代嗎啉基、N-硫代嗎啉基、二氫吡啶基、四氫吡啶基、四氫呋喃基、四氫哌喃基、二氫噻唑基、四氫噻唑基、四氫異噻唑基、二氫基、六氫氮雜卓基、四氫二氮雜卓基、四氫噠基、六氫嘧啶基、二氧戊環基、二基、氮丙啶基、二氧戊環基、氧雜環庚烷基、硫基、噻基(thiinyl)及噻基。 The term "non-aromatic monocyclic heterocyclic group" includes a 3 to 8 membered ring and is, for example, a 4 member, a 5 member or a 6 membered ring. Examples are dioxanyl, thietyl, oxiranyl, oxetanyl, oxa sulfur , azetidinyl, thiaalkyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl, piperidinyl, piperidin , morpholinyl, N-morpholinyl, thiomorpholinyl, N-thiomorpholinyl, dihydropyridyl, tetrahydropyridyl, tetrahydrofuranyl, tetrahydropyranyl, dihydrothiazolyl, Tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrogen Base, hexahydroazepine, tetrahydrodiazepine, tetrahydroanthracene Base, hexahydropyrimidinyl, dioxolane, two Base, aziridine, dioxolanyl, oxetanyl, sulfur Base Thiinyl and thio base.

兩個或兩個以上環之非芳族雜環基之實例包括9至14員基團，且實例為吲哚啉基、異吲哚啉基、烷基及異烷基。 Examples of the non-aromatic heterocyclic group of two or more rings include a 9 to 14 member group, and examples are a porphyrin group, an isoindolyl group, Alkyl and different alkyl.

術語「烷氧基」包括其中氧原子經以上「烷基」取代之基團。實例為甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、第三丁氧基、異丁氧基、第二丁氧基、戊氧基、異戊氧基及己氧基。 The term "alkoxy" includes groups wherein the oxygen atom is substituted by the above "alkyl". Examples are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, second butoxy, pentyloxy, isopentyloxy And hexyloxy.

在一個實施例中，「烷氧基」為甲氧基、乙氧基、正丙氧基、異丙氧基或第三丁氧基。 In one embodiment, "alkoxy" is methoxy, ethoxy, n-propoxy, isopropoxy or tert-butoxy.

術語「烯氧基」包括其中氧原子經以上「烯基」取代之基團。實例為乙烯基氧基、烯丙基氧基、1-丙烯基氧基、2-丁烯基氧基、2- 戊烯基氧基、2-己烯基氧基、2-庚烯基氧基及2-辛烯基氧基。 The term "alkenyloxy" includes groups wherein the oxygen atom is substituted by the above "alkenyl". Examples are vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2- Pentenyloxy, 2-hexenyloxy, 2-heptenyloxy and 2-octenyloxy.

術語「炔氧基」包括其中氧原子經以上「炔基」取代之基團。 實例為乙炔基氧基、1-丙炔基氧基、2-丙炔基氧基、2-丁炔基氧基、2-戊炔基氧基、2-己炔基氧基、2-庚炔基氧基及2-辛炔基氧基。 The term "alkynyloxy" includes groups wherein the oxygen atom is substituted by the above "alkynyl". Examples are ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptyl Alkynyloxy and 2-octynyloxy.

術語「鹵烷基」包括其中一或多個附接至以上「烷基」之一或多碳原子之氫原子經一或多個以上「鹵素」置換之基團。實例為單氟甲基、單氟乙基、單氟丙基、二氟甲基、二氟乙基、二氟丙基、三氟甲基、三氟乙基、三氟丙基、五氟丙基、單氯甲基、單氯乙基、單氯丙基、二氯甲基、二氯乙基、二氯丙基、三氯甲基、三氯乙基、三氯丙基、五氯丙基、1-氟乙基、2-氟乙基、1,1-二氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、1-氯乙基、2-氯乙基、1,1-二氯乙基、2,2-二氯乙基、2,2,2-三氯乙基、1,2-二溴乙基、1,1,1-三氟丙-2-基及2,2,3,3,3-五氟丙基。實例為單氟甲基、二氟甲基、三氟甲基、1-氟乙基、1,1-二氟乙基及2,2-二氟乙基。實例為單氟甲基、二氟甲基、1-氟乙基、1,1-二氟乙基及2,2-二氟乙基。 The term "haloalkyl" includes groups in which one or more hydrogen atoms attached to one or more of the above "alkyl" atoms are replaced by one or more "halogens". Examples are monofluoromethyl, monofluoroethyl, monofluoropropyl, difluoromethyl, difluoroethyl, difluoropropyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, pentafluoropropyl Base, monochloromethyl, monochloroethyl, monochloropropyl, dichloromethyl, dichloroethyl, dichloropropyl, trichloromethyl, trichloroethyl, trichloropropyl, pentachloropropane Base, 1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-chloroethyl, 2 -chloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl, 1,2-dibromoethyl, 1,1,1-three Fluorin-2-yl and 2,2,3,3,3-pentafluoropropyl. Examples are monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl and 2,2-difluoroethyl. Examples are monofluoromethyl, difluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl and 2,2-difluoroethyl.

術語「鹵烯基」包括其中一或多個附接至以上「烯基」之一或多個碳原子之氫原子經一或多個以上「鹵素」置換之基團。實例為單氟乙烯基、單氟烯丙基、單氟丙烯基、二氟乙烯基、二氟烯丙基及二氟丙烯基。 The term "haloalkenyl" includes groups in which one or more hydrogen atoms attached to one or more carbon atoms of the above "alkenyl" are replaced by one or more "halogen". Examples are monofluorovinyl, monofluoroallyl, monofluoropropenyl, difluorovinyl, difluoroallyl and difluoropropenyl.

術語「鹵炔基」包括其中一或多個附接至以上「炔基」之一或多個碳原子之氫原子經一或多個以上「鹵素」置換之基團。實例為氟乙炔基、單氟丙炔基、二氟丙炔基、單氟丁炔基、氯乙炔基、單氯丙炔基、單氯丁炔基及二氯丙炔基。 The term "haloalkynyl" includes groups in which one or more hydrogen atoms attached to one or more carbon atoms of the above "alkynyl" are replaced by one or more "halogen". Examples are fluoroethynyl, monofluoropropynyl, difluoropropynyl, monofluorobutynyl, chloroethynyl, monochloropropynyl, monochlorobutynyl and dichloropropynyl.

術語「鹵烷氧基」包括其中氧原子經以上「鹵烷基」取代之基團。實例為單氟甲氧基、單氟乙氧基、二氟甲氧基、1,1-二氟乙氧基、2,2-二氟乙氧基、三氟甲氧基、三氯甲氧基、2,2,2-三氟乙氧基及 三氯乙氧基。 The term "haloalkoxy" includes groups wherein the oxygen atom is substituted by the above "haloalkyl". Examples are monofluoromethoxy, monofluoroethoxy, difluoromethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, trifluoromethoxy, trichloromethoxy Base, 2,2,2-trifluoroethoxy group and Trichloroethoxy.

在一個實施例中，「鹵烷氧基」為二氟甲氧基、2,2,2-二氟乙氧基、三氟甲氧基、2,2,2-三氟乙氧基或三氯甲氧基。 In one embodiment, "haloalkoxy" is difluoromethoxy, 2,2,2-difluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or tri Chloromethoxy.

術語「氰烷氧基」包括其中以上「烷氧基」經氰基取代之基團。實例為氰甲氧基及氰乙氧基。 The term "cyanoalkoxy" includes groups wherein the above "alkoxy" is substituted with a cyano group. Examples are cyanoxy and cyanoethoxy.

術語「烷氧基烷基」包括其中以上「烷基」經以上「烷氧基」取代之基團。實例為甲氧基甲基、甲氧基乙基及乙氧基甲基。 The term "alkoxyalkyl" includes groups wherein the above "alkyl" is substituted by the above "alkoxy". Examples are methoxymethyl, methoxyethyl and ethoxymethyl.

術語「烷氧基烷氧基」包括其中以上「烷氧基」經以上「烷氧基」取代之基團。實例為甲氧基甲氧基、甲氧基乙氧基、乙氧基甲氧基及乙氧基乙氧基。 The term "alkoxyalkoxy" includes groups wherein the above "alkoxy" is substituted by the above "alkoxy". Examples are methoxymethoxy, methoxyethoxy, ethoxymethoxy and ethoxyethoxy.

術語「環烷基烷氧基」包括其中以上「烷氧基」經以上「環烷基」取代之基團。實例為環丙基甲氧基、環丙基乙氧基、環丁基甲氧基及環丁基乙氧基。 The term "cycloalkylalkoxy" includes groups wherein the above "alkoxy" is substituted by the above "cycloalkyl". Examples are cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy and cyclobutylethoxy.

術語「烷基羰基」包括其中羰基經以上「烷基」取代之基團。實例為甲基羰基、乙基羰基、正丙基羰基、異丙基羰基、第三丁基羰基、異丁基羰基、第二丁基羰基、戊基羰基、異戊基羰基及己基羰基。實例為甲基羰基、乙基羰基及正丙基羰基。 The term "alkylcarbonyl" includes groups wherein the carbonyl group is substituted by the above "alkyl". Examples are methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, t-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl and hexylcarbonyl. Examples are methylcarbonyl, ethylcarbonyl and n-propylcarbonyl.

術語「烯基羰基」包括其中羰基經以上「烯基」取代之基團。實例為乙烯基羰基、丙烯基羰基及丁烯基羰基。 The term "alkenylcarbonyl" includes groups wherein the carbonyl group is substituted by the above "alkenyl". Examples are vinylcarbonyl, propylenecarbonyl and butenylcarbonyl.

術語「炔基羰基」包括其中羰基經以上「炔基」取代之基團。實例為乙炔基羰基、丙炔基羰基及丁炔基羰基。 The term "alkynylcarbonyl" includes groups wherein the carbonyl group is substituted with the above "alkynyl". Examples are ethynylcarbonyl, propynylcarbonyl and butynylcarbonyl.

術語「單烷胺基」包括其中附接至胺基之氮原子之氫原子經以上「烷基」置換之基團。實例為甲胺基、乙胺基及異丙胺基。 The term "monoalkylamino group" includes a group in which a hydrogen atom to which a nitrogen atom of an amine group is substituted by the above "alkyl group". Examples are methylamino, ethylamino and isopropylamino.

在一個實施例中，「單烷胺基」為甲胺基或乙胺基。 In one embodiment, "monoalkylamino" is methylamino or ethylamino.

術語「二烷胺基」包括其中附接至胺基之氮原子之兩個氫原子經兩個以上「烷基」置換之基團。此兩個烷基可相同或不同。實例為 二甲胺基、二乙胺基、N,N-二異丙胺基、N-甲基-N-乙胺基及N-異丙基-N-乙胺基。 The term "dialkylamino" includes a group in which two hydrogen atoms of a nitrogen atom attached to an amine group are replaced by two or more "alkyl groups". These two alkyl groups may be the same or different. An example is Dimethylamino, diethylamino, N,N-diisopropylamino, N-methyl-N-ethylamino and N-isopropyl-N-ethylamino.

在一個實施例中，「二烷胺基」為二甲胺基或二乙胺基。 In one embodiment, the "dialkylamino" is dimethylamino or diethylamino.

術語「烷基磺醯基」包括其中磺醯基經以上「烷基」取代之基團。實例為甲磺醯基、乙磺醯基、丙磺醯基、異丙磺醯基、第三丁磺醯基、異丁磺醯基及第二丁磺醯基。 The term "alkylsulfonyl" includes groups wherein the sulfonyl group is substituted by the above "alkyl". Examples are methanesulfonyl, ethylsulfonyl, propanesulfonyl, isopropylsulfonyl, tributylsulfonyl, isobutylsulfonyl and second butanesulfonyl.

在一個實施例中，「烷基磺醯基」為甲磺醯基或乙磺醯基。 In one embodiment, "alkylsulfonyl" is methylsulfonyl or ethylsulfonyl.

術語「烯基磺醯基」包括其中磺醯基經以上「烯基」取代之基團。實例為乙烯磺醯基、丙烯磺醯基及丁烯磺醯基。 The term "alkenylsulfonyl" includes groups wherein the sulfonyl group is substituted by the above "alkenyl". Examples are ethylene sulfonyl, propylene sulfonyl and buten sulfonyl.

術語「炔基磺醯基」包括其中磺醯基經以上「炔基」取代之基團。實例為乙炔磺醯基、丙炔磺醯基及丁炔磺醯基。 The term "alkynylsulfonyl" includes groups wherein the sulfonyl group is substituted by the above "alkynyl". Examples are acetylenesulfonyl, propynylsulfonyl and butynylsulfonyl.

術語「單烷基羰基胺基」包括其中附接至胺基之氮原子之氫原子經以上「烷基羰基」置換之基團。實例為甲基羰基胺基、乙基羰基胺基、丙基羰基胺基、異丙基羰基胺基、第三丁基羰基胺基、異丁基羰基胺基及第二丁基羰基胺基。 The term "monoalkylcarbonylamino group" includes a group in which a hydrogen atom to which a nitrogen atom of an amine group is substituted by the above "alkylcarbonyl group". Examples are methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino and dibutylcarbonylamino.

在一個實施例中，「單烷基羰基胺基」為甲基羰基胺基或乙基羰基胺基。 In one embodiment, "monoalkylcarbonylamino" is methylcarbonylamino or ethylcarbonylamino.

術語「二烷基羰基胺基」包括其中兩個附接至胺基之氮原子之氫原子經兩個以上「烷基羰基」置換之基團。此兩個烷基羰基可相同或不同。實例為二甲基羰基胺基、二乙基羰基胺基及N,N-二異丙基羰基胺基。在一個實施例中，「二烷基羰基胺基」為二甲基羰基胺基或二乙基羰基胺基。 The term "dialkylcarbonylamino" includes a group in which two hydrogen atoms attached to a nitrogen atom of an amine group are replaced by two or more "alkylcarbonyl groups". The two alkylcarbonyl groups may be the same or different. Examples are dimethylcarbonylamino, diethylcarbonylamino and N,N-diisopropylcarbonylamino. In one embodiment, "dialkylcarbonylamino" is dimethylcarbonylamino or diethylcarbonylamino.

術語「單烷基磺醯胺基」包括其中附接至胺基之氮原子之氫原子經以上「烷基磺醯基」置換之基團。實例為甲磺醯胺基、乙磺醯胺基、丙磺醯胺基、異丙磺醯胺基、第三丁磺醯胺基、異丁磺醯胺胺基及第二丁磺醯胺基。在一個實施例中，「單烷基磺醯胺基」為甲磺醯 胺基或乙磺醯胺基。 The term "monoalkylsulfonylamino" includes a group in which a hydrogen atom of a nitrogen atom attached to an amine group is replaced by the above "alkylsulfonyl group". Examples are methanesulfonamide, etidylamine, propiamine, isopropylsulfonylamine, tributylsulfonamide, isobutylsulfonamide, and butyl sulfonamide . In one embodiment, "monoalkylsulfonylamino" is methylsulfonate Amino or ethanesulfonylamino.

術語「二烷基磺醯胺基」包括其中兩個附接至胺基之氮原子之氫原子經兩個以上「烷基磺醯基」置換之基團。此兩個烷基磺醯基可相同或不同。實例為二甲磺醯胺基、二乙磺醯胺基及N,N-二異丙磺醯胺基。在一個實施例中，「二烷基磺醯胺基」為二甲磺醯胺基或二乙磺醯胺基。 The term "dialkylsulfonylamino" includes a group in which two hydrogen atoms attached to a nitrogen atom of an amine group are replaced by two or more "alkylsulfonyl groups". The two alkylsulfonyl groups may be the same or different. Examples are dimethylsulfonamide, diethylsulfonylamino and N,N-diisopropylsulfonylamino. In one embodiment, the "dialkylsulfonylamino" is dimethylsulfonylamino or diethylsulfonylamino.

術語「烷基亞胺基」包括其中附接至亞胺基之氮原子之氫原子經以上「烷基」置換之基團。實例為甲基亞胺基、乙基亞胺基、正丙基亞胺基及異丙基亞胺基。 The term "alkylimine group" includes a group in which a hydrogen atom attached to a nitrogen atom of an imido group is substituted by the above "alkyl group". Examples are methylimido, ethylimido, n-propylimino and isopropylimino.

術語「烯基亞胺基」包括其中附接至亞胺基之氮原子之氫原子經以上「烯基」置換之基團。實例為乙烯基亞胺基及丙烯基亞胺基。 The term "alkenyl imine group" includes a group in which a hydrogen atom attached to a nitrogen atom of an imido group is substituted with the above "alkenyl group". Examples are vinylimido groups and propenidoimine groups.

術語「炔基亞胺基」包括其中附接至亞胺基之氮原子之氫原子經以上「炔基」置換之基團。實例為乙炔基亞胺基及丙炔基亞胺基。 The term "alkynylene" includes a group in which a hydrogen atom attached to a nitrogen atom of an imide group is substituted with the above "alkynyl group". Examples are ethynylimido and propynylimino groups.

術語「烷基羰基胺基」包括其中附接至亞胺基之氮原子之氫原子經以上「烷基羰基」置換之基團。實例為甲基羰基胺基、乙基羰基胺基、正丙基羰基胺基及異丙基羰基胺基。 The term "alkylcarbonylamino group" includes a group in which a hydrogen atom attached to a nitrogen atom of an imido group is substituted with the above "alkylcarbonyl group". Examples are methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino and isopropylcarbonylamino.

術語「烯基羰基胺基」包括其中附接至亞胺基之氮原子之氫原子經以上「烯基羰基」置換之基團。實例為乙烯基羰基胺基及丙烯基羰基胺基。 The term "alkenylcarbonylamino" includes a group in which a hydrogen atom attached to a nitrogen atom of an imide group is substituted with the above "alkenylcarbonyl group". Examples are vinylcarbonylamino and propenylcarbonylamino.

術語「炔基羰基胺基」包括其中附接至亞胺基之氮原子之氫原子經以上「炔基羰基」置換之基團。實例為乙炔基羰基胺基及丙炔基羰基胺基。 The term "alkynylcarbonylamino" includes a group in which a hydrogen atom attached to a nitrogen atom of an imido group is substituted with the above "alkynylcarbonyl group". Examples are ethynylcarbonylamino and propynylcarbonylamino.

術語「烷氧基亞胺基」包括其中附接至亞胺基之氮原子之氫原子經以上「烷氧基」置換之基團。實例為甲氧基亞胺基、乙氧基亞胺基、正丙氧基亞胺基及異丙氧基亞胺基。 The term "alkoxyimino" includes a group in which a hydrogen atom attached to a nitrogen atom of an imido group is substituted with the above "alkoxy". Examples are methoxyimino, ethoxyimino, n-propoxyimino and isopropoxyimino.

術語「烯氧基亞胺基」包括其中附接至亞胺基之氮原子之氫原 子經以上「烯氧基」置換之基團。實例為乙烯氧基亞胺基及丙烯氧基亞胺基。 The term "alkenyloxyimido" includes a hydrogen source in which a nitrogen atom attached to an imine group is attached. A group substituted by the above "alkenyloxy group". Examples are ethyleneoxyimine groups and propyleneoxyimine groups.

術語「炔氧基亞胺基」包括其中附接至亞胺基之氮原子之氫原子經以上「炔氧基」置換之基團。實例為乙炔氧基亞胺基及丙炔氧基亞胺基。 The term "alkynyloxyimine group" includes a group in which a hydrogen atom to which a nitrogen atom attached to an imido group is substituted by the above "alkynyloxy group". Examples are ethynyloxyimido and propynyloxyimido.

術語「烷基羰氧基」包括其中氧原子經以上「烷基羰基」取代之基團。實例為甲基羰氧基、乙基羰氧基、丙基羰氧基、異丙基羰氧基、第三丁基羰氧基、異丁基羰氧基及第二丁基羰氧基。在一個實施例中，「烷基羰氧基」為甲基羰氧基或乙基羰氧基。 The term "alkylcarbonyloxy" includes a group in which an oxygen atom is substituted with the above "alkylcarbonyl group". Examples are methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy and dibutylcarbonyloxy. In one embodiment, "alkylcarbonyloxy" is methylcarbonyloxy or ethylcarbonyloxy.

術語「烯基羰氧基」包括其中氧原子經以上「烯基羰基」取代之基團。實例為乙烯基羰氧基及丙烯基羰氧基。 The term "alkenylcarbonyloxy" includes groups wherein the oxygen atom is substituted with the above "alkenylcarbonyl". Examples are vinyl carbonyloxy and propylenecarbonyloxy.

術語「炔基羰氧基」包括其中氧原子經以上「炔基羰基」取代之基團。實例為乙炔基羰氧基及丙炔基羰氧基。 The term "alkynylcarbonyloxy" includes a group wherein an oxygen atom is substituted with the above "alkynylcarbonyl". Examples are ethynylcarbonyloxy and propynylcarbonyloxy.

術語「烷氧基羰基」包括其中羰基經以上「烷氧基」取代之基團。實例為甲氧基羰基、乙氧基羰基、丙氧基羰基、異丙氧羰基、第三丁氧基羰基、異丁氧羰基、第二丁氧基羰基、戊氧基羰基、異戊氧基羰基及己氧基羰基。在一個實施例中，「烷氧基羰基」為甲氧基羰基、乙氧基羰基或丙氧基羰基。 The term "alkoxycarbonyl" includes groups wherein the carbonyl group is substituted by the above "alkoxy". Examples are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, isobutoxycarbonyl, second butoxycarbonyl, pentyloxycarbonyl, isopentyloxy Carbonyl and hexyloxycarbonyl. In one embodiment, "alkoxycarbonyl" is methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl.

術語「烯氧基羰基」包括其中羰基經以上「烯氧基」取代之基團。實例為乙烯氧基羰基、丙烯氧基羰基及丁烯氧基羰基。 The term "alkenyloxycarbonyl" includes a group wherein the carbonyl group is substituted by the above "alkenyloxy group". Examples are ethyleneoxycarbonyl, propyleneoxycarbonyl and butenyloxycarbonyl.

術語「炔氧基羰基」包括其中羰基經以上「炔氧基」取代之基團。實例為乙炔氧基羰基、丙炔氧基羰基及丁炔氧基羰基。 The term "alkynyloxycarbonyl" includes groups wherein the carbonyl group is substituted by the above "alkynyloxy group". Examples are ethynyloxycarbonyl, propynyloxycarbonyl and butynyloxycarbonyl.

術語「烷基硫基」包括其中附接至硫基之硫原子之氫原子經以上「烷基」置換之基團。實例為甲基硫基、乙基硫基、正丙基硫基、異丙基硫基、第三丁基硫基及異丁基硫基。 The term "alkylthio" includes a group in which a hydrogen atom attached to a sulfur atom of a sulfur group is replaced by the above "alkyl group". Examples are methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio and isobutylthio.

術語「氰基烷基硫基」包括其中以上「烷基硫基」經氰基取代 之基團。實例為氰基甲基硫基、氰基乙基硫基及氰基丙基硫基。 The term "cyanoalkylthio" includes the above "alkylthio" substituted by cyano The group. Examples are cyanomethylthio, cyanoethylthio and cyanopropylthio.

術語「烯基硫基」包括其中附接至硫基之硫原子之氫原子經以上「烯基」置換之基團。實例為乙烯基硫基、丙烯基硫基及丁烯基硫基。 The term "alkenylthio" includes a group in which a hydrogen atom attached to a sulfur atom of a sulfur group is replaced by the above "alkenyl group". Examples are vinylthio, propenylthio and butenylthio.

術語「炔基硫基」包括其中附接至硫基之硫原子之氫原子經以上「炔基」置換之基團。實例為乙炔基硫基、丙炔基硫基及丁炔基硫基。 The term "alkynylthio" includes a group in which a hydrogen atom attached to a sulfur atom of a sulfur group is replaced by the above "alkynyl group". Examples are ethynylthio, propynylthio and butynylthio.

術語「烷基亞磺醯基」包括其中亞磺醯基經以上「烷基」取代之基團。實例為甲基亞磺醯基、乙基亞磺醯基、正丙基亞磺醯基及異丙基亞磺醯基。 The term "alkylsulfinyl" includes groups wherein the sulfinyl group is substituted by the above "alkyl". Examples are methylsulfinyl, ethylsulfinyl, n-propylsulfinyl and isopropylsulfinyl.

術語「烯基亞磺醯基」包括其中亞磺醯基經以上「烯基」取代之基團。實例為乙烯基亞磺醯基、丙烯基亞磺醯基及丁烯基亞磺醯基。 The term "alkenylsulfinyl" includes groups wherein the sulfinyl group is substituted by the above "alkenyl". Examples are vinylsulfinyl, propenylsulfinyl and butenylsulfinyl.

術語「炔基亞磺醯基」包括其中亞磺醯基經以上「炔基」取代之基團。實例為乙炔基亞磺醯基、丙炔基亞磺醯基及丁炔基亞磺醯基。 The term "alkynylsulfinyl" includes groups wherein the sulfinyl group is substituted by the above "alkynyl". Examples are ethynyl sulfinyl, propynyl sulfinyl and butynyl sulfinyl.

術語「單烷基胺甲醯基」包括其中附接至胺甲醯基之氮原子之氫原子經以上「烷基」置換之基團。實例為甲基胺甲醯基、乙基胺甲醯基、正丙基胺甲醯基及異丙基胺甲醯基。 The term "monoalkylaminecarbamyl" includes a group in which a hydrogen atom attached to a nitrogen atom of an aminomethyl group is substituted by the above "alkyl group". Examples are methylamine methyl thiol, ethylamine methyl sulfhydryl, n-propylamine carbhydryl and isopropylamine carbhydryl.

術語「二烷基胺甲醯基」包括其中兩個附接至胺甲醯基之氮原子之氫原子經兩個以上「烷基」置換之基團。此兩個烷基可相同或不同。實例為二甲基胺甲醯基、二乙基胺甲醯基及N-甲基-N-乙基胺甲醯基。 The term "dialkylaminecarbamyl" includes a group in which two hydrogen atoms attached to a nitrogen atom of an aminomethyl group are replaced by two or more "alkyl groups". These two alkyl groups may be the same or different. Examples are dimethylamine carbaryl, diethylamine carbhydryl and N-methyl-N-ethylaminecarbamyl.

術語「單烷基胺磺醯基」包括其中附接至胺磺醯基之氮原子之氫原子經以上「烷基」置換之基團。實例為甲基胺磺醯基、乙基胺磺醯基、正丙基胺磺醯基及異丙基胺磺醯基。 The term "monoalkylamine sulfonyl" includes a group in which a hydrogen atom attached to a nitrogen atom of an amine sulfonyl group is substituted by the above "alkyl group". Examples are methylamine sulfonyl, ethylamine sulfonyl, n-propylamine sulfonyl and isopropylamine sulfonyl.

術語「二烷基胺磺醯基」包括其中兩個附接至胺磺醯基之氮原子之氫原子經兩個以上「烷基」置換之基團。此兩個烷基可相同或不同。實例為二甲基胺磺醯基、二乙基胺磺醯基及N-甲基-N-乙基胺磺醯基。 The term "dialkylamine sulfonyl" includes a group in which two hydrogen atoms attached to a nitrogen atom of an amine sulfonyl group are replaced by two or more "alkyl groups". These two alkyl groups may be the same or different. Examples are dimethylamine sulfonyl, diethylamine sulfonyl and N-methyl-N-ethylamine sulfonyl.

術語「三烷基矽烷基」包括其中矽原子經三個以上「烷基」取代之基團。此三個烷基可相同或不同。實例為三甲基矽烷基、三乙基矽烷基及第三丁基二甲基矽烷基。 The term "trialkylsulfanyl" embraces radicals in which the ruthenium atom is substituted with three or more "alkyl" groups. These three alkyl groups may be the same or different. Examples are trimethyldecyl, triethyldecyl and tert-butyldimethylalkyl.

術語「亞烷基」包括來源於藉由自相同碳原子移除兩個氫原子之烷烴的二價基團。實例為亞甲基、亞乙基、亞丙基、亞異丙基、亞丁基、亞戊基及亞己基。 The term "alkylene" includes divalent groups derived from an alkane having two hydrogen atoms removed from the same carbon atom. Examples are methylene, ethylene, propylene, isopropylidene, butylene, pentylene and hexylene.

「烯基羰基胺基」、「烷氧基烯氧基」、「烯基硫基」及「烯基胺基」之烯基部分意謂以上「烯基」。 The alkenyl moiety of "alkenylcarbonylamino", "alkoxyalkenyloxy", "alkenylthio" and "alkenylamino" means the above "alkenyl".

「炔基羰基胺基」、「烷氧基炔氧基」、「炔基硫基」及「炔基胺基」之炔基部分意謂以上「炔基」。 The alkynyl moiety of "alkynylcarbonylamino", "alkoxyalkynyloxy", "alkynylthio" and "alkynylamino" means the above "alkynyl".

「羥烷基」、「羥基烷氧基」、「單烷基羰基胺基」、「二烷基羰基胺基」、「單烷胺基」、「二烷胺基」、「胺基烷基」、「烷氧基烯氧基」、「烷氧基炔氧基」、「烷基羰基」、「單烷基胺甲醯基」、「二烷基胺甲醯基」、「羥烷基胺甲醯基」、「烷氧基胺基」、「烷基硫基」、「單烷基磺醯胺基」、「二烷基磺醯胺基」、「烷磺醯基烷胺基」、「烷磺醯基亞胺基」、「烷基亞磺醯基」、「烷基亞磺醯基胺基」、「烷基亞磺醯基烷胺基」、「烷基亞磺醯基亞胺基」、「單烷基胺磺醯基」、「二烷基胺磺醯基」、「芳族碳環基烷基」、「非芳族碳環基烷基」、「芳族雜環基烷基」及「非芳族雜環基烷基」、「芳族碳環烷基氧基」、「非芳族碳環烷基氧基」、「芳族雜環烷基氧基」及「非芳族雜環烷基氧基」、「芳族碳環烷基氧基羰基」、「非芳族碳環烷基氧基羰基」、「芳族雜環烷基氧基羰基」及「非芳族雜環烷基氧基羰基」、「芳族碳環烷基氧基烷基」、「非 芳族碳環烷基氧基烷基」、「芳族雜環烷基氧基烷基」及「非芳族雜環烷基氧基烷基」、「芳族碳環基烷基胺基」、「非芳族碳環基烷基胺基」、「芳族雜環基烷基胺基」、「非芳族雜環基烷基胺基」、「芳族碳環基烷基胺甲醯基」、「非芳族碳環基烷基胺甲醯基」、「芳族雜環基烷基胺甲醯基」及「非芳族雜環基烷基胺甲醯基」及「環烷基烷基」中之烷基部分意謂以上「烷基」。 "Hydroxyalkyl", "hydroxyalkoxy", "monoalkylcarbonylamino", "dialkylcarbonylamino", "monoalkylamino", "dialkylamino", "aminoalkyl" "Alkoxyalkenyloxy", "alkoxyalkynyloxy", "alkylcarbonyl", "monoalkylaminecarbamyl", "dialkylaminecarbamyl", "hydroxyalkyl" "Aminomethyl", "alkoxyamino", "alkylthio", "monoalkylsulfonylamino", "dialkylsulfonylamino", "alkylsulfonylalkylamine" "Alkylsulfonimido", "alkylsulfinyl", "alkylsulfinylamino", "alkylsulfinylalkylamine", "alkylsulfinyl" "Imino", "monoalkylamine sulfonyl", "dialkylamine sulfonyl", "aromatic carbocyclyl", "non-aromatic carbocyclyl", "aromatic" Cycloalkyl" and "non-aromatic heterocycloalkyl", "aromatic carboalkyloxy", "non-aromatic carboalkyloxy", "aromatic heterocycloalkyloxy" And "non-aromatic heterocycloalkyloxy", "aromatic carbocyclic alkyloxycarbonyl", "non-aromatic Carbocyclic alkyloxycarbonyl group "," aromatic heterocyclic oxycarbonyl group "and" non-aromatic heterocyclic oxycarbonyl group "," aromatic carbocyclic alkyloxy group "," non- Aromatic carboalkylalkyloxyalkyl", "aromatic heterocycloalkyloxyalkyl" and "non-aromatic heterocycloalkyloxyalkyl", "aromatic carbocyclylalkylamine" "Non-aromatic carbocyclylalkylamine", "aromatic heterocyclylalkylamino", "non-aromatic heterocyclylalkylamino", "aromatic carbocyclylalkylamine" ", non-aromatic carbocyclic alkylamine-methyl fluorenyl", "aromatic heterocyclic alkylamine-methyl fluorenyl" and "non-aromatic heterocyclic alkylamine-methyl fluorenyl" and "naphthene" The alkyl moiety in the alkyl group means the above "alkyl group".

術語「芳族碳環烷基」包括經一或多個以上「芳族碳環基」取代之烷基。實例為苯甲基、苯乙基、苯丙基、二苯甲基、三苯甲基、萘甲基及下式之基團： The term "aromatic carbocyclic alkyl" embraces alkyl substituted with one or more "aromatic carbocyclic groups". Examples are benzyl, phenethyl, phenylpropyl, benzhydryl, trityl, naphthylmethyl and the groups of the formula:

在一個實施例中，「芳族碳環烷基」為苯甲基、苯乙基或二苯甲基。 In one embodiment, the "aromatic carbocyclic alkyl group" is benzyl, phenethyl or diphenylmethyl.

術語「非芳族碳環基烷基」包括經一或多個以上「非芳族碳環基」取代之烷基。另外，「非芳族碳環基烷基」包括其中其烷基部分經一或多個以上「芳族碳環基」取代之「非芳族碳環烷基」。實例為環丙基甲基、環丁基甲基、環戊基甲基、環己基甲基及下式之基團： The term "non-aromatic carbocyclylalkyl" includes alkyl substituted with one or more "non-aromatic carbocyclic groups". Further, the "non-aromatic carbocyclic alkyl group" includes a "non-aromatic carbocyclic alkyl group" in which an alkyl moiety thereof is substituted with one or more "aromatic carbocyclic groups". Examples are cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and the groups of the formula:

術語「芳族雜環基烷基」包括經一或多個以上「芳族雜環基」取代之烷基。另外，「芳族雜環基烷基」包括其中其烷基部分經一或 多個以上「芳族碳環基」及/或「非芳族碳環基」取代之「芳族雜環基烷基」。實例為吡啶基甲基、呋喃基甲基、咪唑基甲基、吲哚基甲基、苯并噻吩基甲基、唑基甲基、異唑基甲基、噻唑基甲基、異噻唑基甲基、吡唑基乙基、異吡唑基甲基、吡咯啶基甲基、苯并唑基甲基及下式之基團： The term "aromatic heterocyclylalkyl" includes alkyl substituted with one or more "aromatic heterocyclic groups". Further, the "aromatic heterocyclic alkyl group" includes an "aromatic heterocycloalkylene" in which an alkyl moiety is substituted by one or more "aromatic carbocyclic groups" and/or "non-aromatic carbocyclic groups". base". Examples are pyridylmethyl, furylmethyl, imidazolylmethyl, decylmethyl, benzothienylmethyl, Azylmethyl, different Azylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benzo Azolylmethyl group and the group of the formula:

術語「非芳族雜環基烷基」包括經一或多個以上「非芳族雜環基」取代之烷基。另外，「非芳族雜環基烷基」包括其中其烷基部分經一或多個以上「芳族碳環基」、「非芳族碳環基」及/或「芳族雜環基」取代之「非芳族雜環基烷基」。實例為四氫哌喃基甲基、嗎啉基甲基、嗎啉基乙基、哌啶基甲基、哌基甲基及下式之基團： The term "non-aromatic heterocyclylalkyl" includes alkyl substituted with one or more "non-aromatic heterocyclic groups". Further, the "non-aromatic heterocyclic alkyl group" includes those in which the alkyl moiety is subjected to one or more "aromatic carbocyclic groups", "non-aromatic carbocyclic groups" and/or "aromatic heterocyclic groups". Substituted "non-aromatic heterocyclylalkyl". Examples are tetrahydropyranylmethyl, morpholinylmethyl, morpholinylethyl, piperidinylmethyl, piperidine a methyl group and a group of the formula:

術語「芳族碳環烷基氧基」包括經一或多個以上「芳族碳環基」取代之烷氧基。實例為苯甲氧基、苯乙氧基、苯丙氧基、二苯甲氧基、三苯甲氧基、萘甲氧基及下式之基團： The term "aromatic carbocyclic alkyloxy" includes alkoxy groups substituted with one or more "aromatic carbocyclic groups". Examples are benzyloxy, phenethyloxy, phenylpropoxy, diphenylmethoxy, triphenylmethoxy, naphthylmethoxy and the groups of the formula:

術語「非芳族碳環烷基氧基」包括經一或多個以上「非芳族碳 環基」取代之烷氧基。另外，「非芳族碳環烷基氧基」包括其中其烷基部分經一或多個以上「芳族碳環基」取代之「非芳族碳環烷基氧基」。實例為環丙基甲氧基、環丁基甲氧基、環戊基甲氧基、環己基甲氧基及下式之基團： The term "non-aromatic carboalkylalkyloxy" includes alkoxy groups substituted with one or more "non-aromatic carbocyclic groups". Further, the "non-aromatic carboalkylalkyloxy group" includes a "non-aromatic carbocyclic alkyloxy group" in which an alkyl moiety thereof is substituted with one or more "aromatic carbocyclic groups". Examples are cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy and the groups of the formula:

術語「芳族雜環烷基氧基」包括經一或多個以上「芳族雜環基」取代之烷氧基。另外，「芳族雜環烷基氧基」包括其中其烷基部分經一或多個以上「芳族碳環基」及/或「非芳族碳環基」取代之「芳族雜環烷基氧基」。實例為吡啶基甲氧基、呋喃基甲氧基、咪唑基甲氧基、吲哚基甲氧基、苯并噻吩基甲氧基、唑基甲氧基、異唑基甲氧基、噻唑基甲氧基、異噻唑基甲氧基、吡唑基甲氧基、異吡唑基甲氧基、吡咯啶基甲氧基、苯并唑基甲氧基及下式之基團： The term "aromatic heterocycloalkyloxy" includes alkoxy substituted by one or more "aromatic heterocyclic groups". Further, the "aromatic heterocycloalkyloxy group" includes an "aromatic heterocycloalkane in which an alkyl moiety thereof is substituted with one or more "aromatic carbocyclic groups" and/or "non-aromatic carbocyclic groups". Baseoxy". Examples are pyridylmethoxy, furylmethoxy, imidazolylmethoxy, fluorenylmethoxy, benzothienylmethoxy, Azyl methoxy Azylmethoxy, thiazolylmethoxy, isothiazolylmethoxy, pyrazolylmethoxy, isopyrazolylmethoxy, pyrrolidinylmethoxy, benzo Azolylmethoxy group and a group of the formula:

術語「非芳族雜環烷基氧基」包括經一或多個以上「非芳族雜環基」取代之烷氧基。另外，「非芳族雜環烷基氧基」包括其中其烷基部分經一或多個以上「芳族碳環基」、「非芳族碳環基」及/或「芳族雜環基」取代之「非芳族雜環烷基氧基」。實例為四氫哌喃基甲氧基、嗎啉基甲氧基、嗎啉基乙氧基、哌啶基甲氧基、哌基甲氧基及下式之基團：[化學式18] The term "non-aromatic heterocycloalkyloxy" includes alkoxy substituted with one or more "non-aromatic heterocyclic groups". Further, the "non-aromatic heterocycloalkyloxy group" includes an alkyl moiety thereof having one or more "aromatic carbocyclic groups", "non-aromatic carbocyclic groups" and/or "aromatic heterocyclic groups". "Substituted "non-aromatic heterocycloalkyloxy group". Examples are tetrahydropyranylmethoxy, morpholinylmethoxy, morpholinylethoxy, piperidinylmethoxy, piperidine a methoxy group and a group of the formula: [Chemical Formula 18]

術語「芳族碳環基烷氧基羰基」包括經一或多個以上「芳族碳環基」取代之烷氧基羰基。實例為苯甲氧羰基、苯乙氧羰基、苯丙氧羰基、二苯甲氧羰基、三苯甲氧羰基、萘甲氧羰基及下式之基團： The term "aromatic carbocyclyl alkoxycarbonyl" includes alkoxycarbonyl groups substituted with one or more "aromatic carbocyclic groups". Examples are benzyloxycarbonyl, phenethoxycarbonyl, phenylpropoxycarbonyl, diphenylmethoxycarbonyl, triphenylmethoxycarbonyl, naphthylmethoxycarbonyl and the groups of the formula:

術語「非芳族碳環烷基氧基羰基」包括經一或多個以上「非芳族碳環基」取代之烷氧基羰基。另外，「非芳族碳環烷基氧基羰基」包括其中其烷基部分經一或多個以上「芳族碳環基」取代之「非芳族碳環烷基氧基羰基」。實例為環丙基甲氧基羰基、環丁基甲氧基羰基、環戊基甲氧基羰基、環己基甲氧基羰基及下式之基團： The term "non-aromatic carboalkyloxycarbonyl" includes alkoxycarbonyl groups substituted with one or more "non-aromatic carbocyclic groups". Further, the "non-aromatic carboalkylalkyloxycarbonyl group" includes a "non-aromatic carbocyclic alkyloxycarbonyl group" in which an alkyl moiety thereof is substituted with one or more "aromatic carbocyclic groups". Examples are cyclopropylmethoxycarbonyl, cyclobutylmethoxycarbonyl, cyclopentylmethoxycarbonyl, cyclohexylmethoxycarbonyl and groups of the formula:

術語「芳族雜環基烷氧基羰基」包括經一或多個以上「芳族雜環基」取代之烷氧基羰基。另外，「芳族雜環基烷氧基羰基」包括其中其烷基部分經一或多個以上「芳族碳環基」及/或「非芳族碳環基」取代之「芳族雜環基烷氧基羰基」。實例為吡啶基甲氧基羰基、呋喃基甲氧基羰基、咪唑基甲氧基羰基、吲哚基甲氧基羰基、苯并噻吩基甲氧基羰基、唑基甲氧基羰基、異唑基甲氧基羰基、噻唑基 甲氧基羰基、異噻唑基甲氧基羰基、吡唑基甲氧基羰基、異吡唑基甲氧基羰基、吡咯啶基甲氧基羰基、苯并唑基甲氧基羰基及下式之基團： The term "aromatic heterocyclylalkoxycarbonyl" includes alkoxycarbonyl substituted by one or more "aromatic heterocyclic groups". Further, the "aromatic heterocyclic alkoxycarbonyl group" includes an "aromatic heterocyclic ring" in which an alkyl moiety thereof is substituted with one or more "aromatic carbocyclic groups" and/or "non-aromatic carbocyclic groups". Alkoxycarbonyl". Examples are pyridylmethoxycarbonyl, furylmethoxycarbonyl, imidazolylmethoxycarbonyl, fluorenylmethoxycarbonyl, benzothienylmethoxycarbonyl, Azoliylmethoxycarbonyl, different Azylmethoxycarbonyl, thiazolylmethoxycarbonyl, isothiazolylmethoxycarbonyl, pyrazolylmethoxycarbonyl, isopyrazolylmethoxycarbonyl, pyrrolidinylmethoxycarbonyl, benzo Azolylmethoxycarbonyl and a group of the formula:

術語「非芳族雜環基烷氧基羰基」包括經一或多個以上「非芳族雜環基」取代之烷氧基羰基。另外，「非芳族雜環基烷氧基羰基」包括其中其烷基部分經一或多個以上「芳族碳環基」、「非芳族碳環基」及/或「芳族雜環基」取代之「非芳族雜環基烷氧基羰基」。實例為四氫哌喃基甲氧基羰基、嗎啉基甲氧基羰基、嗎啉基乙氧基羰基、哌啶基甲氧基羰基、哌基甲氧基羰基及下式之基團： The term "non-aromatic heterocyclylalkoxycarbonyl" includes alkoxycarbonyl substituted by one or more "non-aromatic heterocyclic groups". Further, the "non-aromatic heterocyclic alkoxycarbonyl group" includes an alkyl moiety having one or more "aromatic carbocyclic groups", "non-aromatic carbocyclic groups" and/or "aromatic heterocyclic rings". The "non-aromatic heterocyclic alkoxycarbonyl group" substituted by a group. Examples are tetrahydropyranylmethoxycarbonyl, morpholinylmethoxycarbonyl, morpholinylethoxycarbonyl, piperidinylmethoxycarbonyl, piperidine a methoxycarbonyl group and a group of the formula:

術語「芳族碳環烷基氧基烷基」包括經一或多個以上「芳族碳環基」取代之烷氧基烷基。實例為苯甲氧基甲基、苯乙氧基甲基、苯丙氧基甲基、二苯甲氧基甲基、三苯甲氧基甲基、萘甲氧基甲基及下式之基團：[化學式23] The term "aromatic carboalkylalkylalkyl" embraces alkoxyalkyl substituted with one or more "aromatic carbocyclyl" groups. Examples are benzyloxymethyl, phenethyloxymethyl, phenylpropoxymethyl, diphenylmethoxymethyl, tritylmethoxymethyl, naphthylmethoxymethyl and the formula Group: [Chemical Formula 23]

術語「非芳族碳環烷基氧基烷基」包括經一或多個以上「非芳族碳環基」取代之烷氧基烷基。另外，「非芳族碳環烷基氧基烷基」包括其中附接至非芳族碳環基之烷基部分經一或多個以上「芳族碳環基」取代之「非芳族碳環烷基氧基烷基」。實例為環丙基甲氧基甲基、環丁基甲氧基甲基、環戊基甲氧基甲基、環己基甲氧基甲基及下式之基團： The term "non-aromatic carboalkylalkyloxyalkyl" includes alkoxyalkyl substituted with one or more "non-aromatic carbocyclic groups". Further, the "non-aromatic carboalkylalkyloxyalkyl group" includes a "non-aromatic carbon in which an alkyl moiety attached to a non-aromatic carbocyclic group is substituted with one or more "aromatic carbocyclic groups". Cycloalkyloxyalkyl". Examples are cyclopropylmethoxymethyl, cyclobutylmethoxymethyl, cyclopentylmethoxymethyl, cyclohexylmethoxymethyl and the groups of the formula:

術語「芳族雜環烷基氧基烷基」包括經一或多個以上「芳族雜環基」取代之烷氧基烷基。另外，「芳族雜環烷基氧基烷基」包括其中附接至芳族雜環基之烷基部分經一或多個以上「芳族碳環基」及/或「非芳族碳環基」取代之「芳族雜環烷基氧基烷基」。實例為吡啶基甲氧基甲基、呋喃基甲氧基甲基、咪唑基甲氧基甲基、吲哚基甲氧基甲基、苯并噻吩基甲氧基甲基、唑基甲氧基甲基、異唑基甲氧基甲基、噻唑基甲氧基甲基、異噻唑基甲氧基甲基、吡唑基甲氧基甲基、異吡唑基甲氧基甲基、吡咯啶基甲氧基甲基、苯并唑基甲氧基甲基及下式之基團：[化學式25] The term "aromatic heterocycloalkyloxyalkyl" includes alkoxyalkyl substituted by one or more "aromatic heterocyclic groups". Further, the "aromatic heterocycloalkyloxyalkyl group" includes an alkyl moiety in which an aromatic heterocyclic group is attached via one or more "aromatic carbocyclic groups" and/or "non-aromatic carbocyclic rings". The "aromatic heterocycloalkyloxyalkyl group" substituted by a group. Examples are pyridylmethoxymethyl, furylmethoxymethyl, imidazolylmethoxymethyl, fluorenylmethoxymethyl, benzothienylmethoxymethyl, Azyl methoxymethyl, different Azylmethoxymethyl, thiazolylmethoxymethyl, isothiazolylmethoxymethyl, pyrazolylmethoxymethyl, isopyrazolylmethoxymethyl, pyrrolidinylmethoxy Methyl, benzo Azolylmethoxymethyl group and a group of the formula: [Chemical Formula 25]

術語「非芳族雜環烷基氧基烷基」包括經一或多個以上「非芳族雜環基」取代之烷氧基烷基。另外，「非芳族雜環烷基氧基烷基」包括其中附接至非芳族雜環基之烷基部分經一或多個以上「芳族碳環基」、「非芳族碳環基」及/或「芳族雜環基」取代之「非芳族雜環烷基氧基烷基」。實例為四氫哌喃基甲氧基甲基、嗎啉基甲氧基甲基、嗎啉基乙氧基甲基、哌啶基甲氧基甲基、哌基甲氧基甲基及下式之基團： The term "non-aromatic heterocycloalkyloxyalkyl" includes alkoxyalkyl substituted by one or more "non-aromatic heterocyclic groups". Further, the "non-aromatic heterocycloalkyloxyalkyl group" includes an alkyl moiety in which a non-aromatic heterocyclic group is attached via one or more "aromatic carbocyclic groups", "non-aromatic carbocyclic rings""Non-aromaticheterocycloalkyloxyalkyl" substituted by a "group" and/or an "aromatic heterocyclic group". Examples are tetrahydropyranylmethoxymethyl, morpholinylmethoxymethyl, morpholinylethoxymethyl, piperidinylmethoxymethyl, piperidin a methoxymethyl group and a group of the formula:

術語「芳族碳環烷基胺基」包括其中一或兩個附接至胺基之氮原子之氫原子經以上「芳族碳環烷基」置換之基團。實例為苯甲基胺基、苯乙基胺基、苯丙基胺基、二苯甲基胺基、三苯甲基胺基、萘甲基胺基及二苯甲基胺基。 The term "aromatic carbocyclic alkylamino group" includes a group in which one or two hydrogen atoms attached to the nitrogen atom of the amine group are replaced by the above "aromatic carbocyclic alkyl group". Examples are benzylamino, phenethylamino, phenylpropylamino, benzhydrylamine, tritylamino, naphthylmethylamino and benzhydrylamine.

術語「非芳族碳環烷基胺基」包括其中一或兩個附接至胺基之氮原子之氫原子經以上「非芳族碳環烷基」置換之基團。實例為環丙基甲基胺基、環丁基甲基胺基、環戊基甲基胺基及環己基甲基胺基。 The term "non-aromatic carbocyclic alkylamino group" includes a group in which one or two hydrogen atoms attached to the nitrogen atom of the amine group are replaced by the above "non-aromatic carbocyclic alkyl group". Examples are cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino and cyclohexylmethylamino.

術語「芳族雜環烷基胺基」包括其中一或兩個附接至胺基之氮原子之氫原子經以上「芳族雜環烷基」置換之基團。實例為吡啶基甲基胺基、呋喃基甲基胺基、咪唑基甲基胺基、吲哚基甲基胺基、苯并 噻吩基甲基胺基、唑基甲基胺基、異唑基甲基胺基、噻唑基甲基胺基、異噻唑基甲基胺基、吡唑基甲基胺基、異吡唑基甲基胺基、吡咯啶基甲基胺基及苯并唑基甲基胺基。 The term "aromatic heterocyclic alkylamino group" includes a group in which one or two hydrogen atoms attached to the nitrogen atom of the amine group are replaced by the above "aromatic heterocycloalkyl group". Examples are pyridylmethylamino, furylmethylamino, imidazolylmethylamino, decylmethylamino, benzothienylmethylamino, Azylmethylamino group Azylmethylamino, thiazolylmethylamino, isothiazolylmethylamino, pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolidinylmethylamino and benzo Azylmethylamino group.

術語「非芳族雜環烷基胺基」包括其中一或兩個附接至胺基之氮原子之氫原子經以上「非芳族雜環烷基」置換之基團。實例為四氫哌喃基甲基胺基、嗎啉基乙基胺基、哌啶基甲基胺基及哌基甲基胺基。 The term "non-aromatic heterocycloalkylamino group" includes a group in which one or two hydrogen atoms attached to the nitrogen atom of the amine group are replaced by the above "non-aromatic heterocycloalkyl group". Examples are tetrahydropiperidylmethylamino, morpholinylethylamino, piperidinylmethylamino and piperidin Methylamino group.

術語「芳族碳環烷基胺甲醯基」包括其中一或兩個附接至胺甲醯基之氮原子之氫原子經以上「芳族碳環烷基」置換之基團。實例為苯甲基胺甲醯基、苯乙基胺甲醯基、苯丙基胺甲醯基、二苯甲基胺甲醯基(benzhydrylcarbamoyl)、三苯甲基胺甲醯基、萘甲基胺甲醯基及二苯甲基胺甲醯基(dibenzylcarbamoyl)。 The term "aromatic carboalkylalkylcarbamyl" includes a group in which one or two hydrogen atoms attached to the nitrogen atom of the aminomethyl group are replaced by the above "aromatic carbocyclic alkyl group". Examples are benzylmethylcarbamyl, phenethylamine, phenylpropylamine, phenylpropylamine, benzhydrylcarbamoyl, tritylmethylcarbamyl, naphthylmethyl Aminomethylmercapto and dibenzylcarbamoyl.

術語「非芳族碳環基烷基胺甲醯基」包括其中一或兩個附接至胺甲醯基之氮原子之氫原子經以上「非芳族碳環基烷基」置換之基團。實例為環丙基甲基胺甲醯基、環丁基甲基胺甲醯基、環戊基甲基胺甲醯基及環己基甲基胺甲醯基。 The term "non-aromatic carbocyclic alkylamine-methyl indenyl" includes a group in which one or two hydrogen atoms attached to the nitrogen atom of the aminomethyl group are replaced by the above "non-aromatic carbocyclic alkyl group". . Examples are cyclopropylmethylaminecarbamyl, cyclobutylmethylaminecarbamyl, cyclopentylmethylaminecarbamyl and cyclohexylmethylaminecarbamyl.

術語「芳族雜環基烷基胺甲醯基」包括其中一或兩個附接至胺甲醯基之氮原子之氫原子經以上「芳族雜環基烷基」置換之基團。實例為吡啶基甲基胺甲醯基、呋喃基甲基胺甲醯基、咪唑基甲基胺甲醯基、吲哚基甲基胺甲醯基、苯并噻吩基甲基胺甲醯基、唑基甲基胺甲醯基、異唑基甲基胺甲醯基、噻唑基甲基胺甲醯基、異噻唑基甲基胺甲醯基、吡唑基甲基胺甲醯基、異吡唑基甲基胺甲醯基、吡咯啶基甲基胺甲醯基及苯并唑基甲基胺甲醯基。 The term "aromatic heterocyclic alkylaminecarbamyl" includes a group in which one or two hydrogen atoms attached to the nitrogen atom of the aminomethyl group are substituted by the above "aromatic heterocyclic alkyl group". Examples are pyridylmethylaminecarbamyl, furylmethylaminecarbamyl, imidazolylmethylamine, mercaptomethylamine, mercaptomethylamine, mercaptomethylamine, mercaptomethylamine, mercapto, Azylmethylamine carbenyl, different Azylmethylaminecarbamyl, thiazolylmethylamine, mercaptomethyl, isothiazolylmethylamine, mercaptomethyl, pyrazolylmethylamine, mercapto, isopyrazolylmethylamine, mercapto, pyrrole Pyridylmethylaminecarbamyl and benzo Azylmethylaminecarbamyl.

術語「非芳族雜環基烷基胺甲醯基」包括其中一或兩個附接至胺甲醯基之氮原子之氫原子經以上「非芳族雜環基烷基」置換之基團。實例為四氫哌喃基甲基胺甲醯基、嗎啉基乙基胺甲醯基、哌啶基 甲基胺甲醯基及哌基甲基胺甲醯基。 The term "non-aromatic heterocyclic alkylaminecarbamyl" includes a group in which one or two hydrogen atoms attached to the nitrogen atom of the aminomethyl group are replaced by the above "non-aromatic heterocyclic alkyl group". . Examples are tetrahydropyranylmethylaminecarbamyl, morpholinylethylaminemethylhydrazine, piperidinylmethylaminecarbamyl and piperidin Methylamine carbenyl.

「芳族碳環」、「芳族碳環基氧基」、「芳族碳環基羰基」、「芳族碳環基羰氧基」、「芳族碳環基氧基羰基」、「芳族碳環基羰基胺基」、「芳族碳環基胺基」、「芳族碳環基硫基」及「芳族碳環基磺醯基」、「芳族碳環基胺磺醯基」及「芳族碳環基胺甲醯基」之「芳族碳環」部分意謂以上「芳族碳環基」。 "Aromatic carbocyclic ring", "aromatic carbocyclic oxy group", "aromatic carbocyclic carbonyl group", "aromatic carbocyclic carbonyloxy group", "aromatic carbocyclic oxycarbonyl group", "fang" Group of carbocyclic carbonyl amine groups, "aromatic carbocyclic amine groups", "aromatic carbocyclic thio groups" and "aromatic carbocyclic sulfonyl groups", "aromatic carbocyclic sulfonyl sulfonyl groups" The "aromatic carbocyclic ring" portion of the "aromatic carbocyclic amine carbenyl group" means the above "aromatic carbocyclic group".

術語「芳族碳環基氧基」包括其中氧原子經以上「芳族碳環基」取代之基團。實例為苯氧基及萘氧基。 The term "aromatic carbocyclyloxy" includes a group in which an oxygen atom is substituted by the above "aromatic carbocyclic group". Examples are phenoxy and naphthyloxy.

術語「芳族碳環基羰基」包括其中羰基經以上「芳族碳環基」取代之基團。實例為苯基羰基及萘基羰基。 The term "aromatic carbocyclylcarbonyl" includes groups wherein the carbonyl group is substituted by the above "aromatic carbocyclic group". Examples are phenylcarbonyl and naphthylcarbonyl.

術語「芳族碳環基羰氧基」包括其中羰氧基經以上「芳族碳環基」取代之基團。實例為苯基羰氧基及萘基羰氧基。 The term "aromatic carbocyclic carbonyloxy" includes groups wherein the carbonyloxy group is substituted by the above "aromatic carbocyclic group". Examples are phenylcarbonyloxy and naphthylcarbonyloxy.

術語「芳族碳環基氧基羰基」包括其中羰基經以上「芳族碳環基氧基」取代之基團。實例為苯氧羰基及萘氧羰基。 The term "aromatic carbocyclyloxycarbonyl" includes a group wherein the carbonyl group is substituted with the above "aromatic carbocyclic oxy group". Examples are phenoxycarbonyl and naphthyloxycarbonyl.

術語「芳族碳環基羰基胺基」包括其中一或兩個附接至胺基之氮原子之氫原子經以上「芳族碳環基羰基」置換之基團。實例為苯甲醯胺基及萘基羰基胺基。 The term "aromatic carbocyclic carbonylamino group" includes a group in which one or two hydrogen atoms attached to the nitrogen atom of the amine group are replaced by the above "aromatic carbocyclic carbonyl group". Examples are benzammonium and naphthylcarbonylamino.

術語「芳族碳環基胺基」包括其中一或兩個附接至胺基之氮原子之氫原子經以上「芳族碳環基」置換之基團。實例為苯胺基及萘胺基。 The term "aromatic carbocyclic amino group" includes a group in which one or two hydrogen atoms attached to the nitrogen atom of the amine group are replaced by the above "aromatic carbocyclic group". Examples are anilino and naphthylamino.

術語「芳族碳環基硫基」包括其中附接至硫基之硫原子之氫原子經以上「芳族碳環基」置換之基團。實例為苯基硫基及萘基硫基。 The term "aromatic carbocyclylthio" includes a group in which a hydrogen atom attached to a sulfur atom of a sulfur group is replaced by the above "aromatic carbocyclic group". Examples are phenylthio and naphthylthio.

術語「芳族碳環基磺醯基」包括其中磺醯基經以上「芳族碳環基」取代之基團。實例為苯磺醯基及萘磺醯基。 The term "aromatic carbocyclic sulfonyl" includes a group wherein a sulfonyl group is substituted by the above "aromatic carbocyclic group". Examples are phenylsulfonyl and naphthylsulfonyl.

術語「芳族碳環基胺磺醯基」包括其中一或兩個附接至胺磺醯基之氮原子之氫原子經以上「芳族碳環基」置換之基團。實例為苯胺 磺醯基及萘胺磺醯基。 The term "aromatic carbocyclic sulfonyl sulfonyl" includes a group in which one or two hydrogen atoms attached to the nitrogen atom of the amine sulfonyl group are replaced by the above "aromatic carbocyclic group". Aniline Sulfonyl and naphthylsulfonyl.

術語「芳族碳環基胺甲醯基」包括其中一或兩個附接至胺甲醯基之氮原子之氫原子經以上「芳族碳環基」置換之基團。實例為苯胺甲醯基及萘胺甲醯基。 The term "aromatic carbocyclic amine carbenyl" includes a group in which one or two hydrogen atoms attached to a nitrogen atom of an aminomethyl group are substituted by the above "aromatic carbocyclic group". Examples are aniline mercapto and naphthylcarbinyl.

「非芳族碳環」、「非芳族碳環基氧基」、「非芳族碳環基羰氧基」、「非芳族碳環基羰基」、「非芳族碳環基氧基羰基」、「非芳族碳環基羰基胺基」、「非芳族碳環基胺基」、「非芳族碳環基硫基」、「非芳族碳環基磺醯基」、「非芳族碳環基胺磺醯基」及「非芳族碳環基胺甲醯基」之「非芳族碳環」部分意謂以上「非芳族碳環基」。 "Non-aromatic carbocyclic ring", "non-aromatic carbocyclic oxy group", "non-aromatic carbocyclic carbonyloxy group", "non-aromatic carbocyclic carbonyl group", "non-aromatic carbocyclic oxy group" "carbonyl", "non-aromatic carbocyclic carbonylamino", "non-aromatic carbocyclic amine", "non-aromatic carbocyclic thio", "non-aromatic carbocyclic sulfonyl", " The "non-aromatic carbocyclic group" of the non-aromatic carbocyclic amine sulfonyl group and the "non-aromatic carbocyclic amine carbenyl group" means the above "non-aromatic carbocyclic group".

術語「非芳族碳環基氧基」包括其中氧原子經以上「非芳族碳環基」取代之基團。實例為環丙氧基、環己氧基及環己烯氧基。 The term "non-aromatic carbocyclic oxy group" includes a group in which an oxygen atom is substituted by the above "non-aromatic carbocyclic group". Examples are cyclopropoxy, cyclohexyloxy and cyclohexenyloxy.

術語「非芳族碳環基羰基」包括其中羰基經以上「非芳族碳環基」取代之基團。實例為環丙基羰基、環己基羰基及環己烯基羰基。 The term "non-aromatic carbocyclic carbonyl" includes groups wherein the carbonyl group is substituted by the above "non-aromatic carbocyclic group". Examples are cyclopropylcarbonyl, cyclohexylcarbonyl and cyclohexenylcarbonyl.

術語「非芳族碳環基羰氧基」包括其中羰氧基經以上「非芳族碳環基」取代之基團。實例為環丙基羰氧基、環己基羰基氧基及環己烯基羰氧基。 The term "non-aromatic carbocyclic carbonyloxy" includes groups wherein the carbonyloxy group is substituted by the above "non-aromatic carbocyclic group". Examples are cyclopropylcarbonyloxy, cyclohexylcarbonyloxy and cyclohexenylcarbonyloxy.

術語「非芳族碳環基氧基羰基」包括其中羰基經以上「非芳族碳環基氧基」取代之基團。實例為環丙氧羰基、環己氧羰基及環己烯氧羰基。 The term "non-aromatic carbocyclic oxycarbonyl" includes groups wherein the carbonyl group is substituted by the above "non-aromatic carbocyclic oxy group". Examples are cyclopropoxycarbonyl, cyclohexyloxycarbonyl and cyclohexeneoxycarbonyl.

術語「非芳族碳環基羰基胺基」包括其中一或兩個附接至胺基之氮原子之氫原子經以上「非芳族碳環基羰基」置換之基團。實例為環丙基羰基胺基、環己基羰基胺基及環己烯基羰基胺基。 The term "non-aromatic carbocyclic carbonylamino group" includes a group in which one or two hydrogen atoms attached to the nitrogen atom of the amine group are replaced by the above "non-aromatic carbocyclic carbonyl group". Examples are cyclopropylcarbonylamino, cyclohexylcarbonylamino and cyclohexenylcarbonylamino.

術語「非芳族碳環基胺基」包括其中一或兩個附接至胺基之氮原子之氫原子經以上「非芳族碳環基」置換之基團。實例為環丙胺基、環己胺基及環己烯胺基。 The term "non-aromatic carbocyclic amino group" includes a group in which one or two hydrogen atoms attached to a nitrogen atom of an amine group are replaced by the above "non-aromatic carbocyclic group". Examples are cyclopropylamino, cyclohexylamino and cyclohexenylamino.

術語「非芳族碳環基硫基」包括其中附接至硫基之硫原子之氫 原子經以上「非芳族碳環基」置換之基團。實例為環丙基硫基、環己基硫基及環己烯基硫基。 The term "non-aromatic carbocyclic thio" includes hydrogen in which a sulfur atom attached to a thio group is attached. A group in which an atom is replaced by a "non-aromatic carbocyclic group". Examples are cyclopropylthio, cyclohexylthio and cyclohexenylthio.

術語「非芳族碳環基磺醯基」包括其中磺醯基經以上「非芳族碳環基」取代之基團。實例為環丙基磺醯基、環己基磺醯基及環己烯基磺醯基。 The term "non-aromatic carbocyclic sulfonyl" includes groups wherein the sulfonyl group is substituted by the above "non-aromatic carbocyclic group". Examples are cyclopropylsulfonyl, cyclohexylsulfonyl and cyclohexenylsulfonyl.

術語「非芳族碳環基胺磺醯基」包括其中一或兩個附接至胺磺醯基之氮原子之氫原子經以上「非芳族碳環基」置換之基團。實例為環丙基胺磺醯基、環己基胺磺醯基及環己烯基胺磺醯基。 The term "non-aromatic carbocyclic sulfonyl sulfonyl" includes a group in which one or two hydrogen atoms attached to the nitrogen atom of the amine sulfonyl group are replaced by the above "non-aromatic carbocyclic group". Examples are cyclopropylamine sulfonyl, cyclohexylamine sulfonyl and cyclohexenylamine sulfonyl.

術語「非芳族碳環基胺甲醯基」包括其中一或兩個附接至胺甲醯基之氮原子之氫原子經以上「非芳族碳環基」置換之基團。實例為環丙基胺甲醯基、環己基胺甲醯基及環己烯基胺甲醯基。 The term "non-aromatic carbocyclic amine carbenyl" includes a group in which one or two hydrogen atoms attached to the nitrogen atom of the amine carbenyl group are replaced by the above "non-aromatic carbocyclic group". Examples are cyclopropylaminecarbamyl, cyclohexylaminecarbamyl and cyclohexenylaminecarbamyl.

「芳族雜環」、「芳族雜環基氧基」、「芳族雜環基羰基」、「芳族雜環基羰氧基」、「芳族雜環基氧基羰基」、「芳族雜環羰基胺基」、「芳族雜環胺基」、「芳族雜環基硫基」、「芳族雜環基磺醯基」、「芳族雜環基胺磺醯基」及「芳族雜環基胺甲醯基」之「芳族雜環」部分意謂以上「芳族雜環基」。 "aromatic heterocyclic ring", "aromatic heterocyclic oxy group", "aromatic heterocyclic carbonyl group", "aromatic heterocyclic carbonyloxy group", "aromatic heterocyclic oxycarbonyl group", "aryl" a heterocyclic carbonylamino group, an "aromatic heterocyclic amine group", an "aromatic heterocyclic thio group", an "aromatic heterocyclic sulfonyl group", an "aromatic heterocyclic sulfonyl group", and The "aromatic heterocyclic ring" of the "aromatic heterocyclic amine carbenyl group" means the above "aromatic heterocyclic group".

環B中之「芳族雜環」之實例為吡啶、吡、嘧啶、噠及唑。 Examples of the "aromatic heterocyclic ring" in the ring B are pyridine and pyridyl Pyrimidine and Oxazole.

術語「芳族雜環基氧基」包括其中氧原子經以上「芳族雜環基」取代之基團。實例為吡啶氧基及唑氧基。 The term "aromatic heterocyclic oxy group" includes a group in which an oxygen atom is substituted with the above "aromatic heterocyclic group". Examples are pyridyloxy and Oxazolyloxy.

術語「芳族雜環基羰基」包括其中羰基經以上「芳族雜環基」取代之基團。實例為吡啶羰基及唑羰基。 The term "aromatic heterocyclic carbonyl" includes a group wherein the carbonyl group is substituted by the above "aromatic heterocyclic group". An example is pyridine carbonyl and Azolecarbonyl.

術語「芳族雜環基羰氧基」包括其中羰氧基經以上「芳族雜環基」取代之基團。實例為吡啶羰氧基及唑羰氧基。 The term "aromatic heterocyclic carbonyloxy group" includes a group in which a carbonyloxy group is substituted by the above "aromatic heterocyclic group". Examples are pyridine carbonyloxy and Azole carbonyloxy.

術語「芳族雜環基氧基羰基」包括其中羰基經以上「芳族雜環基氧基」取代之基團。實例為吡啶氧基羰基及唑氧基羰基。 The term "aromatic heterocyclic oxycarbonyl" includes a group wherein the carbonyl group is substituted by the above "aromatic heterocyclic oxy group". An example is pyridyloxycarbonyl and Oxazolylcarbonyl.

術語「芳族雜環羰基胺基」包括其中一或兩個附接至胺基之氮原子之氫原子經以上「芳族雜環基羰基」置換之基團。實例為吡啶羰基胺基及唑羰基胺基。 The term "aromatic heterocyclic carbonylamino group" includes a group in which one or two hydrogen atoms attached to a nitrogen atom of an amine group are replaced by the above "aromatic heterocyclic carbonyl group". Examples are pyridine carbonyl amine groups and Azolecarbonylamino group.

術語「芳族雜環胺基」包括其中一或兩個附接至胺基之氮原子之氫原子經以上「芳族雜環基」置換之基團。實例為吡啶基胺基及唑基胺基。 The term "aromatic heterocyclic amine group" includes a group in which one or two hydrogen atoms attached to a nitrogen atom of an amine group are replaced by the above "aromatic heterocyclic group". Examples are pyridylamino groups and Azylamino group.

術語「芳族雜環基硫基」包括其中附接至硫基之硫原子之氫原子經以上「芳族雜環基」置換之基團。實例為吡啶基硫基及唑基硫基。 The term "aromatic heterocyclic thio" includes a group wherein a hydrogen atom attached to a sulfur atom of a thio group is substituted with the above "aromatic heterocyclic group". Examples are pyridylthio groups and Azoylthio group.

術語「芳族雜環基磺醯基」包括其中磺醯基經以上「芳族雜環基」取代之基團。實例為吡啶基磺醯基及唑基磺醯基。 The term "aromatic heterocyclic sulfonyl" includes a group wherein a sulfonyl group is substituted by the above "aromatic heterocyclic group". An example is pyridylsulfonyl and Azoylsulfonyl.

術語「芳族雜環基胺磺醯基」包括其中一或兩個附接至胺磺醯基之氮原子之氫原子經以上「芳族雜環基」置換之基團。實例為吡啶基胺磺醯基及唑基胺磺醯基。 The term "aromatic heterocyclic sulfonyl sulfonyl" includes a group in which one or two hydrogen atoms attached to the nitrogen atom of the amine sulfonyl group are replaced by the above "aromatic heterocyclic group". An example is pyridylamine sulfonyl and Zozoylamine sulfonyl.

術語「芳族雜環基胺甲醯基」包括其中一或兩個附接至胺甲醯基之氮原子之氫原子經以上「芳族雜環基」置換之基團。實例為吡啶基胺甲醯基及唑基胺甲醯基。 The term "aromatic heterocyclic amine carbenyl" includes a group in which one or two hydrogen atoms attached to a nitrogen atom of an aminomethyl group are substituted by the above "aromatic heterocyclic group". An example is pyridylamine formazan and Azylamine carbenyl.

「非芳族雜環基」、「非芳族雜環基氧基」、「非芳族雜環基羰基」、「非芳族雜環基羰氧基」、「非芳族雜環基氧基羰基」、「非芳族雜環羰基胺基」、「非芳族雜環基胺基」、「非芳族雜環基硫基」、「非芳族雜環基磺醯基」、「非芳族雜環基胺磺醯基」及「非芳族雜環基胺甲醯基」之「非芳族雜環」部分意謂以上「非芳族雜環基」。 "Non-aromatic heterocyclic group", "non-aromatic heterocyclic oxy group", "non-aromatic heterocyclic carbonyl group", "non-aromatic heterocyclic carbonyloxy group", "non-aromatic heterocyclic oxygen group" "Carbocarbonyl", "non-aromatic heterocyclic carbonylamino group", "non-aromatic heterocyclic amine group", "non-aromatic heterocyclic thio group", "non-aromatic heterocyclic sulfonyl group", " The "non-aromatic heterocyclic ring" of the non-aromatic heterocyclic aminesulfonyl group and the "non-aromatic heterocyclic amine carbenyl group" means the above "non-aromatic heterocyclic group".

術語「非芳族雜環基氧基」包括其中氧原子經以上「非芳族雜環基」取代之基團。實例為哌啶基氧基及四氫呋喃基氧基。 The term "non-aromatic heterocyclic oxy group" includes a group in which an oxygen atom is substituted by the above "non-aromatic heterocyclic group". Examples are piperidinyloxy and tetrahydrofuranyloxy.

術語「非芳族雜環基羰基」包括其中羰基經以上「非芳族雜環基」取代之基團。實例為哌啶基羰基及四氫呋喃基羰基。 The term "non-aromatic heterocyclic carbonyl" includes groups wherein the carbonyl group is substituted by the above "non-aromatic heterocyclic group". Examples are piperidinylcarbonyl and tetrahydrofuranylcarbonyl.

術語「非芳族雜環基羰氧基」包括其中羰氧基經以上「非芳族雜環基」取代之基團。實例為哌啶基羰氧基及四氫呋喃基羰氧基。 The term "non-aromatic heterocyclic carbonyloxy group" includes a group in which a carbonyloxy group is substituted by the above "non-aromatic heterocyclic group". Examples are piperidinylcarbonyloxy and tetrahydrofurancarbonyloxy.

術語「非芳族雜環基氧基羰基」包括其中羰基經以上「非芳族雜環基氧基」取代之基團。實例為哌啶基氧基羰基及四氫呋喃基氧基羰基。 The term "non-aromatic heterocyclic oxycarbonyl" includes a group wherein the carbonyl group is substituted by the above "non-aromatic heterocyclic oxy group". Examples are piperidinyloxycarbonyl and tetrahydrofuranyloxycarbonyl.

術語「非芳族雜環羰基胺基」包括其中一或兩個附接至胺基之氮原子之氫原子經以上「非芳族雜環基羰基」置換之基團。實例為哌啶基羰基胺基及四氫呋喃基羰基胺基。 The term "non-aromatic heterocyclic carbonylamino group" includes a group in which one or two hydrogen atoms attached to the nitrogen atom of the amine group are replaced by the above "non-aromatic heterocyclic carbonyl group". Examples are piperidinylcarbonylamino and tetrahydrofuranylcarbonylamino.

術語「非芳族雜環基胺基」包括其中一或兩個附接至胺基之氮原子之氫原子經以上「非芳族雜環基」置換之基團。實例為哌啶基胺基及四氫呋喃基胺基。 The term "non-aromatic heterocyclic amino group" includes a group in which one or two hydrogen atoms attached to a nitrogen atom of an amine group are replaced by the above "non-aromatic heterocyclic group". Examples are piperidinylamino and tetrahydrofuranylamino.

術語「非芳族雜環基硫基」包括其中附接至硫基之硫原子之氫原子經以上「非芳族雜環基」置換之基團。實例為哌啶基硫基及四氫呋喃基硫基。 The term "non-aromatic heterocyclic thio" includes a group in which a hydrogen atom attached to a sulfur atom of a thio group is substituted by the above "non-aromatic heterocyclic group". Examples are piperidinylthio and tetrahydrofuranylthio.

術語「非芳族雜環基磺醯基」包括其中磺醯基經以上「非芳族雜環基」取代之基團。實例為哌啶基磺醯基及四氫呋喃基磺醯基。 The term "non-aromatic heterocyclic sulfonyl" includes a group wherein a sulfonyl group is substituted by the above "non-aromatic heterocyclic group". Examples are piperidinylsulfonyl and tetrahydrofuransulfonyl.

術語「非芳族雜環基胺磺醯基」包括其中一或兩個附接至胺磺醯基之氮原子之氫原子經以上「非芳族雜環基」置換之基團。實例為哌啶基胺磺醯基及四氫呋喃基胺磺醯基。 The term "non-aromatic heterocyclic aminesulfonyl" includes a group in which one or two hydrogen atoms attached to the nitrogen atom of the aminesulfonyl group are replaced by the above "non-aromatic heterocyclic group". Examples are piperidinylsulfonyl and tetrahydrofuranylsulfonyl.

術語「非芳族雜環基胺甲醯基」包括其中一或兩個附接至胺甲醯基之氮原子之氫原子經以上「非芳族雜環基」置換之基團。實例為哌啶基胺甲醯基及四氫呋喃基胺甲醯基。 The term "non-aromatic heterocyclic amine carbhydryl" includes a group in which one or two hydrogen atoms attached to the nitrogen atom of the aminomethyl group are substituted by the above "non-aromatic heterocyclic group". Examples are piperidinylcarbamyl and tetrahydrofuranylcarbinyl.

術語「R2a及R2b連同其所連接之碳原子可形成經取代環烷」包括[化學式27] The term "R 2a and R 2b together with the carbon atom to which they are attached may form a substituted cycloalkane" includes [Chemical Formula 27]

其中R為鹵素或經取代或未經取代烷基，且m為1或2之整數。 Wherein R is halogen or substituted or unsubstituted alkyl, and m is an integer of 1 or 2.

「經取代或未經取代烷基」、「經取代或未經取代烯基」及「經取代或未經取代炔基」之取代基之實例為如下基團。任何可能的位置處之碳原子可經一或多個選自以下基團之取代基取代。 Examples of the substituent of "substituted or unsubstituted alkyl group", "substituted or unsubstituted alkenyl group" and "substituted or unsubstituted alkynyl group" are the following groups. The carbon atom at any possible position may be substituted with one or more substituents selected from the group consisting of the following.

取代基：鹵素、羥基、羧基、胺基、亞胺基、羥胺基、羥亞胺基、甲醯基、甲醯氧基、胺甲醯基、胺磺醯基、硫基、亞磺酸基、磺酸基、硫甲醯基、硫羧基、二硫羧基、胺(硫甲醯)基、氰基、硝基、亞硝基、疊氮基、肼基、脲基、甲脒基、胍基、三烷基矽烷基、烷氧基、烯氧基、炔氧基、鹵烷氧基、烷基羰基、烯基羰基、炔基羰基、單烷胺基、二烷胺基、烷基磺醯基、烯基磺醯基、炔基磺醯基、單烷基羰基胺基、二烷基羰基胺基、單烷基磺醯胺基、二烷基磺醯胺基、烷基亞胺基、烯基亞胺基、炔基亞胺基、烷基羰基胺基、烯基羰基胺基、炔基羰基胺基、烷氧基亞胺基、烯氧基亞胺基、炔氧基亞胺基、烷基羰氧基、烯基羰氧基、炔基羰氧基、烷氧基羰基、烯氧基羰基、炔氧基羰基、烷基硫基、烯基硫基、炔基硫基、烷基亞磺醯基、烯基亞磺醯基、炔基亞磺醯基、單烷基胺甲醯基、二烷基胺甲醯基、單烷基胺磺醯基、二烷基胺磺醯基、芳族碳環基、非芳族碳環基、芳族雜環基、非芳族雜環基、芳族碳環基氧基、非芳族碳環基氧基、芳族雜環基氧基、非芳族雜環基氧基、芳族碳環基羰基、非芳族碳環基羰基、芳族雜環基羰基、非芳族雜環基羰基、芳族碳環基氧基羰基、非芳族碳環基氧基羰基、芳族雜環基氧基羰基、非芳族雜環基氧基羰基、芳族碳環基烷氧基、非芳族碳環基烷氧基、芳族雜環基烷氧基、 非芳族雜環基烷氧基、芳族碳環基烷氧基羰基、非芳族碳環基烷氧基羰基、芳族雜環基烷氧基羰基、非芳族雜環基烷基氧基羰基、芳族碳環基烷基胺基、非芳族碳環基烷基胺基、芳族雜環基烷基胺基、非芳族雜環基烷基胺基、芳族碳環基硫基、非芳族碳環基硫基、芳族雜環基硫基、非芳族雜環基硫基、芳族碳環基磺醯基、非芳族碳環基磺醯基、芳族雜環基磺醯基及非芳族雜環基磺醯基。 Substituents: halogen, hydroxy, carboxy, amine, imine, hydroxylamine, hydroxyimino, methionyl, methyl methoxy, amine carbaryl, amine sulfonyl, thio, sulfinate , sulfonate, thiomethyl, thiol, dithiol, amine (thiomethyl), cyano, nitro, nitroso, azide, sulfhydryl, ureido, formamidine, hydrazine , trialkylalkyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonate Mercapto, alkenylsulfonyl, alkynylsulfonyl, monoalkylcarbonylamino, dialkylcarbonylamino, monoalkylsulfonylamino, dialkylsulfonylamino, alkylimido , alkenylimino, alkynylamino, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, alkoxyimino, alkenyloxyimido, alkynyloxyimine Base, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylthio, alkenylthio, alkynylthio, Alkylsulfinyl, alkenylsulfinyl, alkyne Sulfosyl, monoalkylamine, mercapto, dialkylamine, mercapto, monoalkylamine sulfonyl, dialkylamine sulfonyl, aromatic carbocyclyl, non-aromatic carbocyclyl, Aromatic heterocyclic group, non-aromatic heterocyclic group, aromatic carbocyclic oxy group, non-aromatic carbocyclyloxy group, aromatic heterocyclic oxy group, non-aromatic heterocyclic oxy group, aromatic carbon Cyclocarbonyl, non-aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl, aromatic carbocyclic oxycarbonyl, non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic ring Alkoxycarbonyl group, non-aromatic heterocyclic oxycarbonyl group, aromatic carbocyclic alkoxy group, non-aromatic carbocyclic alkoxy group, aromatic heterocyclic alkoxy group, Non-aromatic heterocyclylalkoxy, aromatic carbocyclic alkoxycarbonyl, non-aromatic carbocyclyl alkoxycarbonyl, aromatic heterocyclylalkoxycarbonyl, non-aromatic heterocyclylalkyloxy Alkylcarbonyl, an aromatic carbocyclic alkylamino group, a non-aromatic carbocyclic alkylamino group, an aromatic heterocyclylalkylamino group, a non-aromatic heterocyclic alkylamino group, an aromatic carbocyclic group Thio group, non-aromatic carbocyclic thio group, aromatic heterocyclic thio group, non-aromatic heterocyclic thio group, aromatic carbocyclic sulfonyl group, non-aromatic carbocyclic sulfonyl group, aromatic Heterocyclylsulfonyl and non-aromatic heterocyclylsulfonyl.

「經取代或未經取代烷基」之取代基之實例為一或多個選自以下取代基α之基團。 Examples of the substituent of the "substituted or unsubstituted alkyl group" are one or more groups selected from the following substituents α.

取代基α為由以下各者組成之群：鹵素、羥基、烷氧基、鹵烷氧基、羥基烷氧基、烷氧基烷氧基、甲醯基、烷基羰基、烯基羰基、炔基羰基、芳族碳環基羰基、非芳族碳環基羰基、芳族雜環基羰基、非芳族雜環基羰基、烷基羰氧基、烯基羰氧基、芳族碳環基羰氧基、非芳族碳環基羰氧基、芳族雜環基羰氧基、非芳族雜環基羰氧基、羧基、烷氧基羰基、胺基、單烷基羰基胺基、二烷基羰基胺基、烯基羰基胺基、炔基羰基胺基、芳族碳環基羰基胺基、非芳族碳環基羰基胺基、芳族雜環羰基胺基、非芳族雜環羰基胺基、單烷胺基、二烷胺基、亞胺基、羥亞胺基、烷氧基胺基、烷基硫基、胺甲醯基、單烷基胺甲醯基、二烷基胺甲醯基、羥烷基胺甲醯基、胺磺醯基、單烷基胺磺醯基、二烷基胺磺醯基、烷基磺醯基、單烷基磺醯胺基、二烷基磺醯胺基、烷磺醯基烷胺基、烷磺醯基亞胺基、烷基亞磺醯基、烷基亞磺醯基胺基、烷基亞磺醯基烷胺基、烷基亞磺醯基亞胺基、氰基、硝基、芳族碳環基、非芳族碳環基、芳族雜環基及非芳族雜環基(芳族碳環、非芳族碳環、芳族雜環及非芳族雜環中之每一者視情況經選自鹵素、烷基、羥基及烷氧基之一或多者取代)。 The substituent α is a group consisting of halogen, hydroxy, alkoxy, haloalkoxy, hydroxyalkoxy, alkoxyalkoxy, indolyl, alkylcarbonyl, alkenylcarbonyl, alkyne Carbonyl group, aromatic carbocyclic carbonyl group, non-aromatic carbocyclic carbonyl group, aromatic heterocyclic carbonyl group, non-aromatic heterocyclic carbonyl group, alkylcarbonyloxy group, alkenylcarbonyloxy group, aromatic carbocyclic group Carbonyloxy, non-aromatic carbocyclic carbonyloxy, aromatic heterocyclic carbonyloxy, non-aromatic heterocyclic carbonyloxy, carboxy, alkoxycarbonyl, amine, monoalkylcarbonylamino, Dialkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, aromatic carbocyclic carbonylamino, non-aromatic carbocyclic carbonylamino, aromatic heterocyclic carbonylamino, non-aromatic Cyclocarbonylamino group, monoalkylamino group, dialkylamino group, imino group, hydroxyimino group, alkoxyamino group, alkylthio group, amine carbaryl group, monoalkylamine formazan group, dioxane Alkylaminomethyl, hydroxyalkylamine methyl sulfonyl, amine sulfonyl, monoalkylamine sulfonyl, dialkylamine sulfonyl, alkylsulfonyl, monoalkylsulfonylamino, Alkylsulfonylamino, alkanesulfonate Alkylamino, alkanesulfonylimido, alkylsulfinyl, alkylsulfinylamino, alkylsulfinylalkylamine, alkylsulfinylimido, cyano , nitro, aromatic carbocyclic group, non-aromatic carbocyclic group, aromatic heterocyclic group and non-aromatic heterocyclic group (aromatic carbocyclic ring, non-aromatic carbocyclic ring, aromatic heterocyclic ring and non-aromatic heterocyclic ring) Each of the rings is optionally substituted with one or more selected from the group consisting of halogen, alkyl, hydroxy and alkoxy.

「經取代或未經取代烷基」之取代基例如為鹵素、羥基及其類似基團。 The substituent of the "substituted or unsubstituted alkyl group" is, for example, a halogen, a hydroxyl group or the like.

「經取代或未經取代烷氧基」、「經取代或未經取代烯基」及「經取代或未經取代炔基」之取代基之實例為選自以上取代基α之一或多者。特定實例為鹵素、羥基及其類似基團。 Examples of the substituent of "substituted or unsubstituted alkoxy group", "substituted or unsubstituted alkenyl group" and "substituted or unsubstituted alkynyl group" are one or more selected from the above substituents α . Particular examples are halogens, hydroxyl groups and the like.

「經取代或未經取代胺基」之取代基之實例為選自以下之一或兩者：烷基、烷基羰基、烯基羰基、炔基羰基、芳族碳環基羰基、非芳族碳環基羰基、芳族雜環基羰基、非芳族雜環基羰基、羥基、烷氧基、烷氧基羰基、芳族碳環基、非芳族碳環基、芳族雜環基及非芳族雜環基及其類似基團。特定實例為烷基、烷基羰基及其類似基團。 Examples of the substituent of the "substituted or unsubstituted amino group" are one or both selected from the group consisting of an alkyl group, an alkylcarbonyl group, an alkenylcarbonyl group, an alkynylcarbonyl group, an aromatic carbocyclic carbonyl group, and a non-aromatic group. a carbocyclic carbonyl group, an aromatic heterocyclic carbonyl group, a non-aromatic heterocyclic carbonyl group, a hydroxyl group, an alkoxy group, an alkoxycarbonyl group, an aromatic carbocyclic group, a non-aromatic carbocyclic group, an aromatic heterocyclic group, and Non-aromatic heterocyclic groups and the like. Specific examples are alkyl groups, alkylcarbonyl groups and the like.

「經取代或未經取代芳族碳環基」、「經取代或未經取代非芳族碳環基」、「經取代或未經取代環烷基」、「經取代或未經取代芳族雜環基」及「經取代或未經取代非芳族雜環基」之「芳族碳環」、「非芳族碳環」、「環烷基」、「芳族雜環」及「非芳族雜環」之取代基之實例包括如下基團。各環上之任何可能的位置處之一或多個原子可經一或多個選自以下基團之取代基取代。 "Substituted or unsubstituted aromatic carbocyclic group", "substituted or unsubstituted non-aromatic carbocyclic group", "substituted or unsubstituted cycloalkyl group", "substituted or unsubstituted aromatic group" "Aromatic carbon ring", "non-aromatic carbocyclic ring", "cycloalkyl group", "aromatic heterocyclic ring" and "non-heterocyclic group" and "substituted or unsubstituted non-aromatic heterocyclic group" Examples of the substituent of the aromatic heterocyclic ring include the following groups. One or more atoms at any possible position on each ring may be substituted with one or more substituents selected from the group consisting of:

取代基：鹵素、羥基、羧基、胺基、亞胺基、羥胺基、羥亞胺基、甲醯基、甲醯氧基、胺甲醯基、胺磺醯基、硫基、亞磺酸基、磺酸基、硫甲醯基、硫羧基、二硫羧基、胺(硫甲醯)基、氰基、硝基、亞硝基、疊氮基、肼基、脲基、甲脒基、胍基、三烷基矽烷基、烷基、烯基、炔基、鹵烷基、烷氧基、烯氧基、炔氧基、鹵烷氧基、烷氧基烷基、烷氧基烷氧基、烷基羰基、烯基羰基、炔基羰基、單烷胺基、二烷胺基、烷基磺醯基、烯基磺醯基、炔基磺醯基、單烷基羰基胺基、二烷基羰基胺基、單烷基磺醯胺基、二烷基磺醯胺基、烷基亞胺基、烯基亞胺基、炔基亞胺基、烷基羰基胺基、烯基羰基胺基、炔基羰基胺基、烷氧基亞胺基、烯氧基亞胺基、炔氧基亞胺基、烷基羰氧基、烯基羰氧基、炔基羰氧基、烷氧基羰基、烯氧基羰基、炔氧基羰基、烷基硫基、烯基硫基、炔基硫基、烷基亞磺醯基、烯基亞磺醯 基、炔基亞磺醯基、單烷基胺甲醯基、二烷基胺甲醯基、單烷基胺磺醯基、二烷基胺磺醯基、芳族碳環基、非芳族碳環基、芳族雜環基、非芳族雜環基、芳族碳環基氧基、非芳族碳環基氧基、芳族雜環基氧基、非芳族雜環基氧基、芳族碳環基羰基、非芳族碳環基羰基、芳族雜環基羰基、非芳族雜環基羰基、芳族碳環基氧基羰基、非芳族碳環基氧基羰基、芳族雜環基氧基羰基、非芳族雜環基氧基羰基、芳族碳環基烷基、非芳族碳環基烷基、芳族雜環基烷基、非芳族雜環基烷基、芳族碳環烷基氧基、非芳族碳環烷基氧基、芳族雜環烷基氧基、非芳族雜環烷基氧基、芳族碳環烷基氧基羰基、非芳族碳環烷基氧基羰基、芳族雜環烷基氧基羰基、非芳族雜環烷基氧基羰基、芳族碳環烷基氧基烷基、非芳族碳環烷基氧基烷基、芳族雜環烷基氧基烷基、非芳族雜環烷基氧基烷基、芳族碳環基烷基胺基、非芳族碳環基烷基胺基、芳族雜環基烷基胺基、非芳族雜環基烷基胺基、芳族碳環基硫基、非芳族碳環基硫基、芳族雜環基硫基、非芳族雜環基硫基、芳族碳環基磺醯基、非芳族碳環基磺醯基、芳族雜環基磺醯基及非芳族雜環基磺醯基。 Substituents: halogen, hydroxy, carboxy, amine, imine, hydroxylamine, hydroxyimino, methionyl, methyl methoxy, amine carbaryl, amine sulfonyl, thio, sulfinate , sulfonate, thiomethyl, thiol, dithiol, amine (thiomethyl), cyano, nitro, nitroso, azide, sulfhydryl, ureido, formamidine, hydrazine , trialkylalkyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy , alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, monoalkylcarbonylamino, dioxane Alkylcarbonylamino, monoalkylsulfonylamino, dialkylsulfonylamino, alkylimino, alkenylimine, alkynylene, alkylcarbonylamino, alkenylcarbonylamino , alkynylcarbonylamino, alkoxyimino, alkenyloxyimido, alkynyloxyimido, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkoxycarbonyl , alkenyloxycarbonyl, alkynyloxycarbonyl, alkylthio Alkenyl group, alkynyl group, acyl alkylsulfinyl, alkenylsulfinyl sulfonylurea , alkynyl sulfinyl, monoalkylamine, mercapto, dialkylamine, mercapto, monoalkylamine sulfonyl, dialkylamine sulfonyl, aromatic carbocyclyl, non-aromatic Carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, aromatic carbocyclic oxy group, non-aromatic carbocyclyloxy group, aromatic heterocyclic oxy group, non-aromatic heterocyclic oxy group , an aromatic carbocyclic carbonyl group, a non-aromatic carbocyclic carbonyl group, an aromatic heterocyclic carbonyl group, a non-aromatic heterocyclic carbonyl group, an aromatic carbocyclic oxycarbonyl group, a non-aromatic carbocyclic oxycarbonyl group, Aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl, aromatic carbocyclylalkyl, non-aromatic carbocyclylalkyl, aromatic heterocyclylalkyl, non-aromatic heterocyclic Alkyl, aromatic carbocycloalkyloxy, non-aromatic carboalkyloxy, aromatic heterocycloalkyloxy, non-aromatic heterocycloalkyloxy, aromatic carbocyclic alkyloxycarbonyl , non-aromatic carbocyclic alkyloxycarbonyl, aromatic heterocycloalkyloxycarbonyl, non-aromatic heterocycloalkyloxycarbonyl, aromatic carboalkyloxyalkyl, non-aromatic carbocycloalkane Alkoxyalkyl, aromatic heterocycloalkyloxyalkyl, non-aromatic Alkyloxyalkyl, aromatic carbocyclic alkylamino, non-aromatic carbocyclylalkylamine, aromatic heterocyclylalkylamino, non-aromatic heterocyclylalkylamino, aromatic Group of carbocyclic thio, non-aromatic carbocyclylthio, aromatic heterocyclic thio, non-aromatic heterocyclic thio, aromatic carbocyclic sulfonyl, non-aromatic carbocyclic sulfonium A aryl group, an aromatic heterocyclic sulfonyl group, and a non-aromatic heterocyclic sulfonyl group.

「經取代或未經取代非芳族碳環基」及「經取代或未經取代非芳族雜環基」可經「側氧基」取代。其中附接至相同碳原子之兩個氫原子經如下側氧基置換之基團包括： The "substituted or unsubstituted non-aromatic carbocyclic group" and the "substituted or unsubstituted non-aromatic heterocyclic group" may be substituted by "sideoxy". Groups in which two hydrogen atoms attached to the same carbon atom are replaced by a pendant oxy group include:

環A及環B中之「經取代或未經取代之芳族碳環」、「經取代或未經取代之非芳族碳環」、「經取代或未經取代之芳族雜環」、「經取代或未經取代之非芳族雜環」、「經取代或未經取代之苯」、「經取代或未經 取代之吡啶」、「經取代或未經取代之吡」、「經取代或未經取代之唑」、「經取代或未經取代之嘧啶」或「經取代或未經取代之噠」之取代基之實例包括 "Substituted or unsubstituted aromatic carbocyclic ring", "substituted or unsubstituted non-aromatic carbocyclic ring", "substituted or unsubstituted aromatic heterocyclic ring" in ring A and ring B, "Substituted or unsubstituted non-aromatic heterocyclic ring", "substituted or unsubstituted benzene", "substituted or unsubstituted pyridine", "substituted or unsubstituted pyridyl" ", replaced or unsubstituted Oxazole, "substituted or unsubstituted pyrimidine" or "substituted or unsubstituted hydrazine" Examples of substituents include

(a)選自取代基α之基團，例如鹵素、羥基、烷氧基、甲醯基、烷基羰基、烯基羰基、炔基羰基、芳族碳環基羰基、非芳族碳環基羰基、芳族雜環基羰基、非芳族雜環基羰基、甲醯氧基、烷基羰氧基、烯基羰氧基、炔基羰氧基、芳族碳環基羰氧基、非芳族碳環基羰氧基、芳族雜環基羰氧基、非芳族雜環基羰氧基、羧基、烷氧基羰基、胺甲醯基、胺基、氰基、單烷胺基、二烷胺基及/或烷基磺醯基；(b)未經取代烷基或經一或多個選自取代基α、羥亞胺基及烷氧亞胺基取代之烷基；(c)經一或多個選自取代基α之基團取代之胺基烷基；(d)未經取代烯基或經一或多個選自取代基α之取代基取代之烯基；(e)未經取代炔基或經一或多個選自取代基α之取代基取代之炔基；(f)經一或多個選自取代基α之取代基取代之烷氧基；(g)經一或多個選自取代基α之取代基取代之烷氧基烷氧基；(h)未經取代烯氧基或經一或多個選自取代基α之取代基取代之烯氧基；(i)經一或多個選自取代基α之取代基取代之烷氧基烯氧基；(j)未經取代炔氧基或經一或多個選自取代基α之取代基取代之炔氧基；(k)經一或多個選自取代基α之基團取代之烷氧基炔氧基；(l)未經取代烷基硫基或經一或多個選自取代基α之取代基取代之烷基硫基； (m)未經取代烯基硫基或經一或多個選自取代基α之取代基取代之烯基硫基；(n)未經取代炔基硫基或經一或多個選自取代基α之取代基取代之炔基硫基；(o)經一或多個選自取代基α之取代基取代之單烷胺基；(p)經一或多個選自取代基α之取代基取代之二烷胺基；(q)經一或多個選自取代基α之取代基取代之烯基胺基；(r)經一或多個選自取代基α之取代基取代之炔基胺基；(s)未經取代胺氧基或經一或多個選自取代基α及亞烷基之取代基取代之胺氧基；(t)經一或多個選自取代基α之取代基取代之烷基羰基；(u)經一或多個選自取代基α之取代基取代之烯基羰基；(v)經一或多個選自取代基α之取代基取代之炔基羰基；(w)經一或多個選自取代基α之取代基取代之芳族碳環基羰基；(x)經一或多個選自取代基α之取代基取代之非芳族碳環基羰基；(y)經一或多個選自取代基α之取代基取代之芳族雜環基羰基；(z)經一或多個選自取代基α之取代基取代之非芳族雜環基羰基；(aa)經一或多個選自取代基α之取代基取代之單烷基胺甲醯基；(ab)經一或多個選自取代基α之取代基取代之二烷基胺甲醯基；(ac)經一或多個選自取代基α之取代基取代之烷氧基羰基；(ad)未經取代烷基磺醯基或經一或多個選自取代基α之取代基取代之烷基磺醯基；(ae)未經取代烷基亞磺醯基或經一或多個選自取代基α之取代基取代之烷基亞磺醯基； (af)經一或多個選自取代基α之取代基取代之單烷基胺磺醯基；(ag)經一或多個選自取代基α之取代基取代之二烷基胺磺醯基；(ah)經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之芳族碳環基；(ai)經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族碳環基；(aj)經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之芳族雜環基；(ak)經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族雜環基；(al)未經取代芳族碳環烷基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之芳族碳環烷基；(am)未經取代非芳族碳環烷基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族碳環烷基；(an)未經取代芳族雜環烷基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之芳族雜環烷基；(ao)未經取代非芳族雜環烷基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族雜環烷基；(ap)未經取代芳族碳環基氧基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之芳族碳環基氧基；(aq)未經取代非芳族碳環基氧基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族碳環基氧基；(ar)未經取代芳族雜環基氧基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之芳族雜環基氧基；(as)未經取代非芳族雜環基氧基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族雜環基氧基； (at)未經取代芳族碳環烷基氧基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之芳族碳環烷基氧基；(au)未經取代非芳族碳環烷基氧基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族碳環烷基氧基；(av)未經取代非芳族雜環烷基氧基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族雜環烷基氧基；(aw)未經取代非芳族雜環烷基氧基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族雜環烷基氧基；(ax)未經取代芳族碳環烷基氧基羰基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之芳族碳環烷基氧基羰基；(ay)未經取代非芳族碳環烷基氧基羰基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族碳環烷基氧基羰基；(az)未經取代芳族雜環烷基氧基羰基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之芳族雜環烷基氧基羰基；(ba)未經取代非芳族雜環烷基氧基羰基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族雜環烷基氧基羰基；(bb)未經取代芳族碳環基硫基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之芳族碳環基硫基；(bc)未經取代非芳族碳環基硫基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族碳環基硫基；(bd)未經取代芳族雜環基硫基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之芳族雜環基硫基；(be)未經取代非芳族雜環基硫基或經一或多個選自(bf)取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族雜環基硫基； (bf)未經取代芳族碳環基胺基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之芳族碳環基胺基；(bg)未經取代非芳族碳環基胺基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族碳環基胺基；(bh)未經取代芳族雜環胺基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之芳族雜環胺基；(bi)未經取代非芳族雜環胺基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族雜環胺基；(bj)未經取代芳族碳環烷基胺基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之芳族碳環烷基胺基；(bk)未經取代非芳族碳環烷基胺基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族碳環烷基胺基；(bl)未經取代芳族雜環烷基胺基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之芳族雜環烷基胺基；(bm)未經取代非芳族雜環烷基胺基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族雜環烷基胺基；(bn)未經取代芳族碳環基胺磺醯基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之芳族碳環基胺磺醯基；(bo)未經取代非芳族碳環基胺磺醯基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族碳環基胺磺醯基；(bp)未經取代芳族雜環基胺磺醯基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之芳族雜環基胺磺醯基；(bq)未經取代非芳族雜環基胺磺醯基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族雜環基胺磺醯基；(br)未經取代芳族碳環基磺醯基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之芳族碳環基磺醯基； (bs)未經取代非芳族碳環基磺醯基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族碳環基磺醯基；(bt)未經取代芳族雜環基磺醯基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之芳族雜環基磺醯基；(bu)未經取代非芳族雜環基磺醯基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族雜環基磺醯基；(bv)未經取代芳族碳環基胺甲醯基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之芳族碳環基胺甲醯基；(bw)未經取代非芳族碳環基胺甲醯基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族碳環基胺甲醯基；(bx)未經取代雜環基胺甲醯基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之芳族雜環基胺甲醯基；(by)未經取代非芳族雜環基胺甲醯基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族雜環基胺甲醯基；(bz)未經取代芳族碳環烷基胺甲醯基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之芳族碳環烷基胺甲醯基；(ca)未經取代非芳族碳環烷基胺甲醯基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族碳環烷基胺甲醯基；(cb)未經取代芳族雜環烷基胺甲醯基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之芳族雜環烷基胺甲醯基；(cc)未經取代非芳族雜環烷基胺甲醯基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族雜環烷基胺甲醯基；(cd)未經取代芳族碳環基氧基羰基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之芳族碳環基氧基羰基； (ce)未經取代非芳族碳環基氧基羰基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族碳環基氧基羰基；(cf)未經取代芳族雜環基氧基羰基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之芳族雜環基氧基羰基；(cg)未經取代非芳族雜環基氧基羰基或經一或多個選自取代基α、疊氮基、烷基及鹵烷基之取代基取代之非芳族雜環基氧基羰基；(ch)未經取代伸烷二氧基或經鹵素取代之伸烷二氧基；(ci)側氧基；及(cj)疊氮基。 (a) a group selected from the substituent α, such as a halogen, a hydroxyl group, an alkoxy group, a decyl group, an alkylcarbonyl group, an alkenylcarbonyl group, an alkynylcarbonyl group, an aromatic carbocyclic carbonyl group, a non-aromatic carbocyclic group Carbonyl, aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl, methyl methoxy, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, aromatic carbocyclic carbonyloxy, non Aromatic carbocyclic carbonyloxy, aromatic heterocyclic carbonyloxy, non-aromatic heterocyclic carbonyloxy, carboxy, alkoxycarbonyl, aminemethanyl, amine, cyano, monoalkylamino a dialkylamino group and/or an alkylsulfonyl group; (b) an unsubstituted alkyl group or an alkyl group substituted with one or more substituents selected from the group consisting of a substituent α, a hydroxyimino group and an alkoxyimine group; c) an aminoalkyl group substituted with one or more groups selected from the substituent α; (d) an unsubstituted alkenyl group or an alkenyl group substituted with one or more substituents selected from the substituent α; e) an unsubstituted alkynyl group or an alkynyl group substituted with one or more substituents selected from the substituent α; (f) an alkoxy group substituted with one or more substituents selected from the substituent α; An alkoxy group substituted with one or more substituents selected from the substituent α Alkoxy; (h) unsubstituted alkenyloxy or alkenyloxy substituted by one or more substituents selected from substituent a; (i) substituted with one or more substituents selected from substituent a An alkoxyalkenyloxy group; (j) an unsubstituted alkynyloxy group or an alkynyloxy group substituted with one or more substituents selected from the substituents α; (k) one or more selected from the substituents α a group substituted alkoxyalkynyloxy group; (1) an unsubstituted alkylthio group or an alkylthio group substituted with one or more substituents selected from the substituent α; (m) an unsubstituted alkenylthio group or an alkenylthio group substituted with one or more substituents selected from the substituent α; (n) an unsubstituted alkynylthio group or substituted by one or more selected from Alkynylthio group substituted with a substituent of the group α; (o) a monoalkylamino group substituted with one or more substituents selected from the substituent α; (p) substituted with one or more selected from the substituent α a substituted dialkylamino group; (q) an alkenylamino group substituted with one or more substituents selected from the substituent α; (r) an alkyne substituted with one or more substituents selected from the substituent α (s) an unsubstituted aminooxy group or an amineoxy group substituted with one or more substituents selected from the substituents α and an alkylene group; (t) one or more selected from the substituents α a substituent substituted with an alkylcarbonyl group; (u) an alkenylcarbonyl group substituted with one or more substituents selected from the substituent α; (v) an alkyne substituted with one or more substituents selected from the substituent α a carbonyl group; (w) an aromatic carbocyclic carbonyl group substituted with one or more substituents selected from the substituent α; (x) a non-aromatic carbon substituted with one or more substituents selected from the substituent α a carbonyl group; (y) one or more selected from the group consisting of a substituent α a substituted heterocyclic heterocyclic carbonyl group; (z) a non-aromatic heterocyclic carbonyl group substituted with one or more substituents selected from the substituent α; (aa) one or more selected from the substituents α a substituent substituted with a monoalkylaminecarbamyl group; (ab) a dialkylaminecarbamyl group substituted with one or more substituents selected from the substituent α; (ac) substituted by one or more selected from Alkoxycarbonyl group substituted by a substituent of the group α; (ad) unsubstituted alkylsulfonyl group or alkylsulfonyl group substituted by one or more substituents selected from the substituent α; a substituted alkylsulfinyl group or an alkylsulfinyl group substituted with one or more substituents selected from the substituents α; (af) a monoalkylamine sulfonyl group substituted with one or more substituents selected from the substituent α; (ag) a dialkylamine sulfonium hydrazide substituted with one or more substituents selected from the substituent α (ah) an aromatic carbocyclic group substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group, and a haloalkyl group; (ai) one or more selected from the group consisting of substituents a non-aromatic carbocyclic group substituted with a substituent of an azide group, an alkyl group and a haloalkyl group; (aj) a substituent selected from one or more substituents α, an azide group, an alkyl group and a haloalkyl group a substituted aromatic heterocyclic group; (ak) a non-aromatic heterocyclic group substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group and a haloalkyl group; (al) unsubstituted An aromatic carbocyclic alkyl group or an aromatic carbocyclic alkyl group substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group and a haloalkyl group; (am) an unsubstituted non-aromatic carbon a cycloalkyl group or a non-aromatic carbocyclic alkyl group substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group and a haloalkyl group; (an) an unsubstituted aromatic heterocycloalkyl group Or one or more selected from the group consisting of a substituent α, an azide group, an alkyl group and a haloalkyl group a substituted heteroaromatic heterocycloalkyl group; (ao) an unsubstituted non-aromatic heterocycloalkyl group or substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group, and a haloalkyl group a non-aromatic heterocycloalkyl group; (ap) an unsubstituted aromatic carbocyclyloxy group or an aromatic group substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group and a haloalkyl group a group of carbocyclyloxy groups; (aq) unsubstituted non-aromatic carbocyclyloxy group or non-aryl substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group and a haloalkyl group a carbocyclic oxy group; (ar) an unsubstituted aromatic heterocyclic oxy group or an aromatic hydrazone substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group and a haloalkyl group; a cyclic oxy group; (as) an unsubstituted non-aromatic heterocyclic oxy group or a non-aromatic heterocyclic group substituted with one or more substituents selected from the group consisting of a substituent α, an azide group, an alkyl group, and a haloalkyl group; Cyclooxy group; (at) an unsubstituted aromatic carbocycloalkyloxy group or an aromatic carbocyclic alkyloxy group substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group and a haloalkyl group; (au) an unsubstituted non-aromatic carbocycloalkyloxy group or a non-aromatic carboalkyloxy group substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group and a haloalkyl group (av) an unsubstituted non-aromatic heterocycloalkyloxy group or a non-aromatic heterocycloalkane substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group, and a haloalkyl group; (a) an unsubstituted non-aromatic heterocycloalkyloxy group or a non-aromatic hybrid substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group, and a haloalkyl group; a cycloalkyloxy group; (ax) an unsubstituted aromatic carbocyclic alkyloxycarbonyl group or an aromatic group substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group, and a haloalkyl group Carbocycloalkyloxycarbonyl; (ay) unsubstituted non-aromatic carboalkyloxycarbonyl or substituted by one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group and a haloalkyl group Non-aromatic carbocyclic alkyloxycarbonyl; (az) unsubstituted An aromatic heterocycloalkyloxycarbonyl group or an aromatic heterocycloalkyloxycarbonyl group substituted by one or more substituents selected from the group consisting of a substituent α, an azide group, an alkyl group and a haloalkyl group; (ba) a non-aromatic heterocycloalkyloxycarbonyl group substituted with a non-aromatic heterocycloalkyloxycarbonyl group or substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group, and a haloalkyl group; (bb) an unsubstituted aromatic carbocyclic thio group or an aromatic carbocyclic thio group substituted with one or more substituents selected from the group consisting of a substituent α, an azide group, an alkyl group and a haloalkyl group; (bc An unsubstituted non-aromatic carbocyclylthio group or a non-aromatic carbocyclylthio group substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group and a haloalkyl group; (bd) An unsubstituted aromatic heterocyclic thio group or an aromatic heterocyclic thio group substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group and a haloalkyl group; (be) not a non-aromatic heterocyclic thio group substituted with a non-aromatic heterocyclic thio group or substituted with one or more substituents selected from the group consisting of (bf) substituents a, azide, alkyl and haloalkyl; (bf) an unsubstituted aromatic carbocyclic amino group or an aromatic carbocyclic amino group substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group and a haloalkyl group; An unsubstituted non-aromatic carbocyclic amino group or a non-aromatic carbocyclic amine group substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group and a haloalkyl group; (bh An unsubstituted aromatic heterocyclic amine group or an aromatic heterocyclic amine group substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group and a haloalkyl group; (bi) unsubstituted a non-aromatic heterocyclic amine group or a non-aromatic heterocyclic amine group substituted with one or more substituents selected from the substituents α, azide, alkyl and haloalkyl; (bj) unsubstituted aromatic a carbocyclic alkylamino group or an aromatic carbocyclic alkylamino group substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group and a haloalkyl group; (bk) unsubstituted non-aryl group a family of carbocyclic alkylamino groups or a non-aromatic carbocyclic alkylamino group substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group and a haloalkyl group; (bl) unsubstituted An aromatic heterocycloalkylamino group or one or more selected from the group consisting of substituents α, An aromatic heterocycloalkylamino group substituted with a substituent of a group, an alkyl group and a haloalkyl group; (bm) an unsubstituted non-aromatic heterocyclic alkylamino group or one or more selected from the group consisting of substituents α, a non-aromatic heterocyclic alkylamino group substituted with a substituent of a nitrogen group, an alkyl group and a haloalkyl group; (bn) an unsubstituted aromatic carbocyclic amine sulfonyl group or one or more selected from the substituents α An aromatic carbocyclic sulfonyl group substituted with a substituent of an azide group, an alkyl group and a haloalkyl group; (bo) an unsubstituted non-aromatic carbocyclic sulfonyl group or one or more selected from one or more a non-aromatic carbocyclic sulfonyl group substituted with a substituent of a substituent a, an azide group, an alkyl group and a haloalkyl group; (bp) an unsubstituted aromatic heterocyclic sulfonyl group or one or more An aromatic heterocyclic sulfonyl group substituted with a substituent selected from the substituents α, azide, alkyl and haloalkyl; (bq) unsubstituted non-aromatic heterocyclic sulfonyl group or a non-aromatic heterocyclic sulfonyl group substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group and a haloalkyl group; (br) an unsubstituted aromatic carbocyclic sulfonyl group Or one or more selected from the group consisting of a substituent α, an azide group, an alkyl group and a halogen The group of substituted carbocyclic aromatic acyl sulfo group; (bs) an unsubstituted non-aromatic carbocyclic sulfonyl group or a non-aromatic carbocyclic sulfonate substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group and a haloalkyl group (bt) an unsubstituted aromatic heterocyclic sulfonyl group or an aromatic heterocyclic sulfonate substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group, and a haloalkyl group; (bu) an unsubstituted non-aromatic heterocyclic sulfonyl group or a non-aromatic heterocyclic group substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group, and a haloalkyl group; a sulfonyl group; (bv) an unsubstituted aromatic carbocyclic amine carbenyl group or an aromatic carbocyclic ring substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group, and a haloalkyl group; (bw) unsubstituted non-aromatic carbocyclic amine carbenyl group or substituted by one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group and a haloalkyl group An aromatic carbocyclic amine carbenyl group; (bx) an unsubstituted heterocyclic amine carbenyl group or substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group and a haloalkyl group Aromatic heterocyclic amine carbenyl; (by) unsubstituted non-aromatic heterocyclic group An aminylmethyl group or a non-aromatic heterocyclic aminomethyl group substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group and a haloalkyl group; (bz) an unsubstituted aromatic group a carbocyclic alkylcarbamyl group or an aromatic carbocyclic alkylamine carbenyl group substituted by one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group and a haloalkyl group; (ca) Substituted non-aromatic carboalkylalkylcarbamyl or non-aromatic carbocyclic alkylamine for substitution with one or more substituents selected from the group consisting of substituents a, azide, alkyl and haloalkyl (cb) an unsubstituted aromatic heterocycloalkylaminecarbamyl group or an aromatic heterocycloalkane substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group, and a haloalkyl group; a (meth) unsubstituted non-aromatic heterocyclic alkylaminecarbamyl group or substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group, and a haloalkyl group; a non-aromatic heterocyclic alkylaminecarbamyl group; (cd) an unsubstituted aromatic carbocyclic oxycarbonyl group or substituted with one or more selected from the group consisting of a substituent a, an azide group, an alkyl group, and a haloalkyl group a substituted aromatic carbocyclic oxycarbonyl group; (ce) an unsubstituted non-aromatic carbocyclic oxycarbonyl group or a non-aromatic carbocyclic oxy group substituted with one or more substituents selected from the group consisting of a substituent a, an azide group, an alkyl group and a haloalkyl group a carbonyl group; (cf) an unsubstituted aromatic heterocyclic oxycarbonyl group or an aromatic heterocyclic oxy group substituted with one or more substituents selected from the group consisting of a substituent α, an azide group, an alkyl group, and a haloalkyl group; a carbonyl group; (cg) an unsubstituted non-aromatic heterocyclic oxycarbonyl group or a non-aromatic heterocyclic group substituted with one or more substituents selected from the group consisting of a substituent α, an azide group, an alkyl group, and a haloalkyl group; An oxycarbonyl group; (ch) an unsubstituted alkylene dioxy group or a halogen-substituted alkylene dioxy group; (ci) a pendant oxy group; and (cj) an azide group.

「經取代或未經取代之芳族碳環」、「經取代或未經取代之非芳族碳環」、「經取代或未經取代之苯」、「經取代或未經取代之芳族雜環」、「經取代或未經取代之非芳族雜環」、「經取代或未經取代之吡啶」、「經取代或未經取代之吡」、「經取代或未經取代之唑」、「經取代或未經取代之嘧啶」或「經取代或未經取代之噠」中之各環基可經一或多個選自以上取代基之取代基取代。 "Substituted or unsubstituted aromatic carbocyclic ring", "substituted or unsubstituted non-aromatic carbocyclic ring", "substituted or unsubstituted benzene", "substituted or unsubstituted aromatic"Heterocycle","substituted or unsubstituted non-aromatic heterocycle", "substituted or unsubstituted pyridine", "substituted or unsubstituted pyridyl" ", replaced or unsubstituted Oxazole, "substituted or unsubstituted pyrimidine" or "substituted or unsubstituted hydrazine" Each of the cyclic groups in the above may be substituted with one or more substituents selected from the above substituents.

環A及環B中之「經取代或未經取代之芳族碳環」、「經取代或未經取代之非芳族碳環」、「經取代或未經取代之芳族雜環」、「經取代或未經取代之非芳族雜環」、「經取代或未經取代之苯」、「經取代或未經取代之吡啶」、「經取代或未經取代之吡」、「經取代或未經取代之唑」、「經取代或未經取代之嘧啶」或「經取代或未經取代之噠」之取代基之實例為選自以下中之一或多者：鹵素；氰基；羥基；硝基；羧基； 經一或多個選自取代基α之取代基取代之烷基，未經取代烷基；經一或多個選自取代基α之取代基取代之烯基，未經取代烯基；經一或多個選自取代基α之取代基取代之炔基，未經取代炔基；經一或多個選自取代基α之取代基取代之烷氧基，未經取代烷氧基；經一或多個選自取代基α之取代基取代之烯氧基，未經取代烯氧基；經一或多個選自取代基α之取代基取代之炔氧基，未經取代炔氧基；經一或多個選自取代基α之取代基取代之烷基硫基，未經取代烷基硫基；經一或多個選自取代基α之取代基取代之烯基硫基，未經取代烯基硫基；經一或多個選自取代基α之取代基取代之炔基硫基，未經取代炔基硫基；經一或多個選自取代基α之取代基取代之胺基，未經取代胺基；經一或多個選自取代基α之取代基取代之單烷胺基，未經取代單烷胺基；經一或多個選自取代基α之取代基取代之二烷胺基，未經取代二烷胺基；經一或多個選自取代基α之取代基取代之環烷基胺基，未經取代環烷基胺基； 經一或多個選自取代基α之取代基取代之胺甲醯基，未經取代胺甲醯基；經一或多個選自取代基α之取代基取代之單烷基胺甲醯基，未經取代單烷基胺甲醯基；經一或多個選自取代基α之取代基取代之二烷基胺甲醯基，未經取代二烷基胺甲醯基；經一或多個選自取代基α之取代基取代之烷氧基羰基，未經取代烷氧基羰基；經一或多個選自取代基α、未經取代烷基及經一或多個選自取代基α之取代基取代之烷基之取代基取代之芳族碳環基；未經取代芳族碳環基；經一或多個選自取代基α、未經取代烷基及經一或多個選自取代基α之取代基取代之烷基之取代基取代之非芳族碳環基；未經取代非芳族碳環基；經一或多個選自取代基α、未經取代烷基及經一或多個選自取代基α之取代基取代之烷基之取代基取代之芳族雜環基；未經取代芳族雜環基；經一或多個選自取代基α、未經取代烷基及經一或多個選自取代基α之取代基取代之烷基之取代基取代之非芳族雜環基；及未經取代非芳族雜環基。 "Substituted or unsubstituted aromatic carbocyclic ring", "substituted or unsubstituted non-aromatic carbocyclic ring", "substituted or unsubstituted aromatic heterocyclic ring" in ring A and ring B, "Substituted or unsubstituted non-aromatic heterocyclic ring", "substituted or unsubstituted benzene", "substituted or unsubstituted pyridine", "substituted or unsubstituted pyridyl" ", replaced or unsubstituted Oxazole, "substituted or unsubstituted pyrimidine" or "substituted or unsubstituted hydrazine" Examples of the substituent are one or more selected from the group consisting of halogen; cyano; hydroxy; nitro; carboxy; alkyl substituted by one or more substituents selected from substituent α, unsubstituted An alkyl group; an alkenyl group substituted with one or more substituents selected from the substituent α, an unsubstituted alkenyl group; an alkynyl group substituted with one or more substituents selected from the substituent α, an unsubstituted alkynyl group An alkoxy group substituted with one or more substituents selected from the substituent α, an unsubstituted alkoxy group; an alkenyloxy group substituted with one or more substituents selected from the substituent α, an unsubstituted alkene An oxy group; an alkynyloxy group substituted by one or more substituents selected from the substituent α, an unsubstituted alkynyloxy group; an alkylthio group substituted with one or more substituents selected from the substituent α, a substituted alkylthio group; an alkenylthio group substituted with one or more substituents selected from the substituent α, an unsubstituted alkenylthio group; substituted with one or more substituents selected from the substituent α An alkynylthio group, an unsubstituted alkynylthio group; an amine group substituted with one or more substituents selected from the substituent α, an unsubstituted amine group; a monoalkylamino group substituted with a substituent selected from the substituent α, an unsubstituted monoalkylamino group; a dialkylamine group substituted with one or more substituents selected from the substituent α, an unsubstituted dialkylamine a cycloalkylamino group substituted with one or more substituents selected from the substituent α, an unsubstituted cycloalkylamino group; an amine formazan substituted with one or more substituents selected from the substituent α An unsubstituted aminemethanyl group; a monoalkylamine methyl sulfonyl group substituted with one or more substituents selected from the substituents α, an unsubstituted monoalkylamine methyl sulfhydryl group; one or more selected a dialkylaminecarbamyl group substituted with a substituent of a substituent α, an unsubstituted dialkylaminecarbamyl group; an alkoxycarbonyl group substituted with one or more substituents selected from the substituent α, a substituted alkoxycarbonyl group; an aromatic carbocyclic group substituted with one or more substituents selected from the group consisting of a substituent α, an unsubstituted alkyl group, and an alkyl group substituted with one or more substituents selected from the substituent α An unsubstituted aromatic carbocyclic group; an alkane substituted with one or more substituents selected from the group consisting of a substituent α, an unsubstituted alkyl group, and one or more substituents selected from the substituent α a non-aromatic carbocyclic group substituted with a substituent; an unsubstituted non-aromatic carbocyclic group; one or more selected from the group consisting of a substituent α, an unsubstituted alkyl group, and one or more selected from the substituent α An aromatic heterocyclic group substituted with a substituent of a substituent-substituted alkyl group; an unsubstituted aromatic heterocyclic group; one or more selected from the group consisting of a substituent α, an unsubstituted alkyl group, and one or more selected a non-aromatic heterocyclic group substituted with a substituent of an alkyl group substituted with a substituent of the substituent α; and an unsubstituted non-aromatic heterocyclic group.

在一個實施例中，取代基為選自鹵素、氰基、羥基、烷基、鹵烷基、環烷基烷基、烷氧基、鹵烷氧基、烷氧基烷氧基、氰烷氧基、烯基、鹵烯基、炔基、鹵炔基、烯氧基、炔氧基、烷基硫基、氰基烷基硫基、胺基、單烷胺基、二烷胺基、環烷基胺基及環烷基中之一或多者。 In one embodiment, the substituent is selected from the group consisting of halogen, cyano, hydroxy, alkyl, haloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkoxy, cyanoalkoxy Base, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkenyloxy, alkynyloxy, alkylthio, cyanoalkylthio, amine, monoalkylamino, dialkylamino, ring One or more of an alkylamino group and a cycloalkyl group.

在另一實施例中，取代基為選自鹵素、氰基、烷基、鹵烷基、 烷氧基、鹵烷氧基、環烷基烷氧基、炔氧基中之一或多者。 In another embodiment, the substituent is selected from the group consisting of halogen, cyano, alkyl, haloalkyl, One or more of an alkoxy group, a haloalkoxy group, a cycloalkyl alkoxy group, and an alkynyloxy group.

在另一實施例中，環A之取代基為選自鹵素中之一或多者。 In another embodiment, the substituent of Ring A is one or more selected from the group consisting of halogens.

在另一實施例中，環B之取代基為選自鹵素、氰基、烷基、鹵烷基、烷氧基及鹵烷氧基中之一或多者。 In another embodiment, the substituent of Ring B is one or more selected from the group consisting of halogen, cyano, alkyl, haloalkyl, alkoxy, and haloalkoxy.

在一個實施例中，「經取代或未經取代之環烷基」之取代基為選自取代基α、未經取代烷基及經一或多個選自取代基α之取代基取代之烷基中之一或多者。 In one embodiment, the substituent of the "substituted or unsubstituted cycloalkyl group" is an alkyl group selected from the group consisting of a substituent α, an unsubstituted alkyl group, and a substituent substituted with one or more substituents selected from the substituent α. One or more of the bases.

在另一實施例中，「經取代或未經取代之環烷基」為未經取代環烷基。 In another embodiment, the "substituted or unsubstituted cycloalkyl group" is an unsubstituted cycloalkyl group.

本發明之特定實施例說明於下文中。實施例為下式(IA)至(IM)之化合物： Specific embodiments of the invention are described below. Examples are compounds of the following formula (IA) to (IM):

其中各符號與上文所定義相同，或其醫藥學上可接受之鹽。 Wherein each symbol is the same as defined above, or a pharmaceutically acceptable salt thereof.

在式(IA)、(IB)、(IC)、(IJ)或(IK)化合物之一個實施例中，R2a為烷基或鹵烷氧基。 In one embodiment of the compound of formula (IA), (IB), (IC), (IJ) or (IK), R 2a is alkyl or haloalkoxy.

在式(ID)、(IE)、(IJ)或(IK)化合物之一個實施例中，R2a為鹵素。 In one embodiment of the formula (ID), (IE), (IJ) or (IK) compound, R 2a is halogen.

在式(IL)、(IM)、(IN)或(IO)化合物之一個實施例中，R為鹵素且m為2之整數。 In one embodiment of the compound of formula (IL), (IM), (IN) or (IO), R is halogen and m is an integer of two.

在式(IF)化合物之一個實施例中，R5為鹵素且n為1或2之整數。 In one embodiment of the compound of formula (IF), R 5 is halogen and n is an integer of 1 or 2.

在式(IG)、(IH)或(II)化合物之一個實施例中，R2a為鹵素。 In one embodiment of the compound of formula (IG), (IH) or (II), R 2a is halogen.

在式(IH)化合物之一個實施例中，R2a為烷氧基。 In one embodiment of the compound of formula (IH), R 2a is alkoxy.

式(I)之各符號之特定實施例說明於下文中。此等實施例之所有組合為式(I)化合物之實例。 Specific embodiments of the symbols of formula (I) are described below. All combinations of these examples are examples of compounds of formula (I).

在式(I)中，X為-O-，R3a為鹵烷基，R3b為烷基，R2a為H，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X1)，X為-O-，R3a為CF3，R3b為烷基，R2a為H，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X2)，X為-O-，R3a為CHF2，R3b為H，R2a為鹵素，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X3)，X為-O-，R3a為CHFCH3，R3b為H，R2a為鹵素，R2b為H，且R1為 烷基或鹵烷基(在下文中稱為X4)，X為-O-，R3a為CF2CH3，R3b為H，R2a為鹵素，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X5)，X為-O-，R3a為經烷氧基或環烷基取代之鹵烷基，R3b為H，R2a為鹵素，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X6)，X為-O-，R3a為鹵烷基，R3b為烷基，R2a為鹵素，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X7)，X為-O-，R3a為鹵烷基，R3b為H，R2a為烷基，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X8)，X為-O-，R3a為CHF2，R3b為H，R2a為CH3，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X8)，X為-O-，R3a為CF3，R3b為H，R2a為CH3，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X10)，X為-O-，R3a為鹵烷基，R3b為烷基，R2a為烷基，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X11)，X為-O-，R3a為鹵烷基，R3b為H，R2a為烷氧基，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X12)，X為-O-，R3a為CH2F，R3b為H，R2a為OCH3，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X13)，X為-O-，R3a為CF3，R3b為H，R2a為OCH3，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X14)，X為-O-，R3a為鹵烷基，R3b為烷基，R2a為烷氧基，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X15)，X為-O-，R3a為鹵烷基，R3b為H，R2a為鹵烷氧基，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X16)，X為-O-，R3a為CH2F，R3b為H，R2a為OCH2CF3，R2b為H，且R1為 烷基或鹵烷基(在下文中稱為X17)，X為-O-，R3a為鹵烷基，R3b為烷基，R2a為鹵烷氧基，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X18)，X為-S-，R3a為烷基，R3b為H，R2a為鹵素，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X19)，X為-S-，R3a為CH3或CH2CH3，R3b為H，R2a為鹵素，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X20)，X為-S-，R3a為烷基，R3b為烷基，R2a為鹵素，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X21)，X為-S-，R3a為烷基，R3b為H，R2a為烷氧基，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X22)，X為-S-，R3a為烷基，R3b為烷基，R2a為烷氧基，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X23)，X為-S-，R3a為烷基，R3b為H，R2a為鹵烷氧基，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X24)，X為-S-，R3a為烷基，R3b為烷基，R2a為鹵烷氧基，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X25)，X為-S-，R3a為鹵烷基，R3b為H，R2a為鹵素，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X26)，X為-S-，R3a為CH2F，R3b為H，R2a為鹵素，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X27)，X為-S-，R3a為鹵烷基，R3b為烷基，R2a為鹵素，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X28)，X為-S-，R3a為鹵烷基，R3b為H，R2a為烷氧基，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X29)，X為-S-，R3a為鹵烷基，R3b為烷基，R2a為烷氧基，R2b為H，且R1 為烷基或鹵烷基(在下文中稱為X30)，X為-S-，R3a為鹵烷基，R3b為H，R2a為鹵烷氧基，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X31)，X為-S-，R3a為鹵烷基，R3b為烷基，R2a為鹵烷氧基，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X32)，X為-S-，R3a為鹵烷基，R3b為H，R2a為烷基，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X33)，X為-S-，R3a為鹵烷基，R3b為烷基，R2a為烷基，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X34)，X為-S-，R3a為烷氧基烷基，R3b為H，R2a為鹵素，R2b為H，且R1為烷基或鹵烷基(在下文中稱為X35)，X為-O-， In formula (I), X is -O-, R 3a is haloalkyl, R 3b is alkyl, R 2a is H, R 2b is H, and R 1 is alkyl or haloalkyl (hereinafter referred to as Is X1), X is -O-, R 3a is CF 3 , R 3b is alkyl, R 2a is H, R 2b is H, and R 1 is alkyl or haloalkyl (hereinafter referred to as X2), X is -O-, R 3a is CHF 2 , R 3b is H, R 2a is halogen, R 2b is H, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X3), and X is -O- R 3a is CHFCH 3 , R 3b is H, R 2a is halogen, R 2b is H, and R 1 is alkyl or haloalkyl (hereinafter referred to as X4), X is -O-, and R 3a is CF 2 CH 3 , R 3b is H, R 2a is halogen, R 2b is H, and R 1 is alkyl or haloalkyl (hereinafter referred to as X5), X is -O-, and R 3a is alkoxy Or a cycloalkyl-substituted haloalkyl group, R 3b is H, R 2a is halogen, R 2b is H, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X6), and X is -O-, R 3a is a haloalkyl group, R 3b is an alkyl group, R 2a is a halogen, R 2b is H, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X7), X is -O-, and R 3a is a halogen. alkyl group, R 3b is H, R 2a is alkyl, R 2b is H, and R 1 is alkyl or haloalkyl (hereinafter referred to X8), X -O-, R 3a is CHF 2, R 3b is H, R 2a is CH 3, R 2b is H, and R 1 is alkyl or haloalkyl (hereinafter referred to X8), X is -O-, R 3a is CF 3 , R 3b is H, R 2a is CH 3 , R 2b is H, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X10), X is -O-, and R 3a is a halogen. An alkyl group, R 3b is an alkyl group, R 2a is an alkyl group, R 2b is H, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X11), X is -O-, and R 3a is a haloalkyl group. R 3b is H, R 2a is alkoxy, R 2b is H, and R 1 is alkyl or haloalkyl (hereinafter referred to as X12), X is -O-, and R 3a is CH 2 F, R 3b is H, R 2a is OCH 3 , R 2b is H, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X13), X is -O-, R 3a is CF 3 , and R 3b is H, R 2a is OCH 3 , R 2b is H, and R 1 is alkyl or haloalkyl (hereinafter referred to as X14), X is -O-, R 3a is haloalkyl, R 3b is alkyl, R 2a Is an alkoxy group, R 2b is H, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X15), X is -O-, R 3a is a haloalkyl group, R 3b is H, and R 2a is a halogen. Alkoxy, R 2b is H, and R 1 is alkyl or haloalkyl (hereinafter referred to as X16), X is -O-, R 3a is CH 2 F, and R 3b is H, R 2a is OCH 2 CF 3 , R 2b is H, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X17), X is -O-, R 3a is a haloalkyl group, and R 3b is an alkyl group. R 2a is a haloalkoxy group, R 2b is H, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X18), X is -S-, R 3a is an alkyl group, and R 3b is H, R 2a Is halogen, R 2b is H, and R 1 is alkyl or haloalkyl (hereinafter referred to as X19), X is -S-, R 3a is CH 3 or CH 2 CH 3 , and R 3b is H, R 2a Is halogen, R 2b is H, and R 1 is alkyl or haloalkyl (hereinafter referred to as X20), X is -S-, R 3a is alkyl, R 3b is alkyl, R 2a is halogen, R 2b is H, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X21), X is -S-, R 3a is an alkyl group, R 3b is H, R 2a is an alkoxy group, and R 2b is H. And R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X22), X is -S-, R 3a is an alkyl group, R 3b is an alkyl group, R 2a is an alkoxy group, and R 2b is H, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X23), X is -S-, R 3a is an alkyl group, R 3b is H, R 2a is a haloalkoxy group, R 2b is H, and R 1 Is an alkyl group or a haloalkyl group (hereinafter referred to as X24), X is -S-, R 3a is an alkyl group, R 3b is an alkyl group, and R 2a is Haloalkoxy, R 2b is H, and R 1 is alkyl or haloalkyl (hereinafter referred to as X25), X is -S-, R 3a is haloalkyl, R 3b is H, and R 2a is halogen R 2b is H, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X26), X is -S-, R 3a is CH 2 F, R 3b is H, R 2a is halogen, and R 2b is H, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X27), X is -S-, R 3a is a haloalkyl group, R 3b is an alkyl group, R 2a is a halogen, and R 2b is H, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X28), X is -S-, R 3a is a haloalkyl group, R 3b is H, R 2a is an alkoxy group, R 2b is H, and R 1 Is an alkyl group or a haloalkyl group (hereinafter referred to as X29), X is -S-, R 3a is a haloalkyl group, R 3b is an alkyl group, R 2a is an alkoxy group, R 2b is H, and R 1 is An alkyl or haloalkyl group (hereinafter referred to as X30), X is -S-, R 3a is a haloalkyl group, R 3b is H, R 2a is a haloalkoxy group, R 2b is H, and R 1 is an alkane Or haloalkyl (hereinafter referred to as X31), X is -S-, R 3a is haloalkyl, R 3b is alkyl, R 2a is haloalkoxy, R 2b is H, and R 1 is an alkane or haloalkyl group (hereinafter referred to X32), X is -S-, R 3a alkyl group is a halogen, R 3b is H, R 2a is alkyl , R 2b is H, and R 1 is alkyl or haloalkyl (hereinafter referred to as X33), X is -S-, R 3a alkyl group is a halogen, R 3b is alkyl, R 2a is alkyl, R 2b is H, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X34), X is -S-, R 3a is an alkoxyalkyl group, R 3b is H, R 2a is a halogen, and R 2b is H, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X35), and X is -O-,

R3b為H，n為0，且R1為烷基或鹵烷基(在下文中稱為X36)，X為-O-， R 3b is H, n is 0, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X36), and X is -O-,

R3b為烷基，n為0，且R1為烷基或鹵烷基(在下文中稱為X37)，X為-O-，[化學式32] R 3b is an alkyl group, n is 0, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X37), and X is -O-, [Chemical Formula 32]

R3b為H，n為1，R5為鹵素，且R1為烷基或鹵烷基(在下文中稱為X38)，X為-O-， R 3b is H, n is 1, R 5 is halogen, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X38), and X is -O-,

R3b為烷基，n為1，R5為鹵素，且R1為烷基或鹵烷基(在下文中稱為X39)，X為-O-， R 3b is an alkyl group, n is 1, R 5 is a halogen, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X39), and X is -O-,

R3b為H，n為2，R5為鹵素，且R1為烷基或鹵烷基(在下文中稱為X40)，X為-O-， R 3b is H, n is 2, R 5 is halogen, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X40), and X is -O-,

R3b為烷基，n為2，R5為鹵素，且R1為烷基或鹵烷基(在下文中稱為X41)，X為-S-， R 3b is an alkyl group, n is 2, R 5 is a halogen, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X41), and X is -S-,

R3b為H，n為0，且R1為烷基或鹵烷基(在下文中稱為X42)，X為-S-， R 3b is H, n is 0, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X42), and X is -S-,

R3b為烷基，n為0，且R1為烷基或鹵烷基(在下文中稱為X43)，X為-S-， R 3b is an alkyl group, n is 0, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X43), and X is -S-,

R3b為H，n為1，R5為鹵素，且R1為烷基或鹵烷基(在下文中稱為X44)，X為-S-， R 3b is H, n is 1, R 5 is halogen, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X44), and X is -S-,

R3b為烷基，n為1，R5為鹵素，且R1為烷基或鹵烷基(在下文中稱為X45)，X為-S-，[化學式40] R 3b is an alkyl group, n is 1, R 5 is a halogen, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X45), and X is -S-, [Chemical Formula 40]

R3b為H，n為2，R5為鹵素，且R1為烷基或鹵烷基(在下文中稱為X46)，X為-S-， R 3b is H, n is 2, R 5 is halogen, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X46), and X is -S-,

R3b為烷基，n為2，R5為鹵素，且R1為烷基或鹵烷基(在下文中稱為X47)，X為-S-或-O-，R3a為H或烷基，R3b為H，R2a及R2b連同其所連接之碳原子可形成經1或2個鹵素取代之環烷，且R1為烷基或鹵烷基(在下文中稱為X48)，環A為經取代或未經取代之苯且環B為經取代或未經取代之吡啶(在下文中稱為AB1)，環A為經取代或未經取代之苯且環B為經取代或未經取代之吡(在下文中稱為AB2)，環A為經取代或未經取代之苯且環B為經取代或未經取代之唑(在下文中稱為AB3)，環A為經取代或未經取代之苯且環B為經取代或未經取代之嘧啶或經取代或未經取代之噠(在下文中稱為AB4)，環A為經取代或未經取代之吡啶，且環B為經取代或未經取代之吡啶(在下文中稱為AB5)，環A為經取代或未經取代之吡啶，且環B為經取代或未經取代之吡(在下文中稱為AB6)， 環A為經取代或未經取代之吡啶，且環B為經取代或未經取代之唑(在下文中稱為AB7)，環A為經如F或Cl之鹵素取代之苯，且環B為經一或兩個選自鹵素、氰基、烷基、烷氧基及鹵烷氧基之取代基取代之吡啶(在下文中稱為AB8)，環A為經如F或Cl之鹵素取代之苯，且環B為經一或兩個選自鹵烷基、烷氧基、鹵烷氧基、炔氧基及環烷基烷氧基之取代基取代之吡(在下文中稱為AB9)，環A為經如F或Cl之鹵素取代之苯，且環B為經一或兩個選自烷基及鹵烷基之取代基取代之唑(在下文中稱為AB10)，環A為經如F或Cl之鹵素取代之苯，且環B為經一或兩個選自鹵烷氧基之取代基取代之嘧啶或經一或兩個選自烷氧基之取代基取代之噠(在下文中稱為AB11)，環A為經鹵素取代之吡啶且環B為經一或兩個選自鹵素及氰基之取代基取代之吡啶(在下文中稱為AB12)，環A為經鹵素取代之吡啶且環B為經一或兩個選自烷氧基及鹵烷氧基之取代基取代之吡(在下文中稱為AB13)。式(I)化合物之「X、R3a、R3b、R2a、R2b及R1」及「環A及環B」之組合(X,AB)之實例如下：(X1,AB1)、(X1,AB2)、(X1,AB3)、(X1,AB4)、(X1,AB5)、(X1,AB6)、(X1,AB7)、(X1,AB8)、(X1,AB9)、(X1,AB10)、(X1,AB11)、(X1,AB12)、(X1,AB13)、(X2,AB1)、(X2,AB2)、(X2,AB3)、(X2,AB4)、(X2,AB5)、(X2,AB6)、(X2,AB7)、(X2,AB8)、(X2,AB9)、(X2,AB10)、(X2,AB11)、(X2,AB12)、(X2,AB13)、(X3,AB1)、(X3,AB2)、(X3,AB3)、(X3,AB4)、(X3,AB5)、(X3,AB6)、(X3,AB7)、(X3,AB8)、(X3,AB9)、 (X3,AB10)、(X3,AB11)、(X3,AB12)、(X3,AB13)、(X4,AB1)、(X4,AB2)、(X4,AB3)、(X4,AB4)、(X4,AB5)、(X4,AB6)、(X4,AB7)、(X4,AB8)、(X4,AB9)、(X4,AB10)、(X4,AB11)、(X4,AB12)、(X4,AB13)、(X5,AB1)、(X5,AB2)、(X5,AB3)、(X5,AB4)、(X5,AB5)、(X5,AB6)、(X5,AB7)、(X5,AB8)、(X5,AB9)、(X5,AB10)、(X5,AB11)、(X5,AB12)、(X5,AB13)、(X6,AB1)、(X6,AB2)、(X6,AB3)、(X6,AB4)、(X6,AB5)、(X6,AB6)、(X6,AB7)、(X6,AB8)、(X6,AB9)、(X6,AB10)、(X6,AB11)、(X6,AB12)、(X6,AB13)、(X7,AB1)、(X7,AB2)、(X7,AB3)、(X7,AB4)、(X7,AB5)、(X7,AB6)、(X7,AB7)、(X7,AB8)、(X7,AB9)、(X7,AB10)、(X7,AB11)、(X7,AB12)、(X7,AB13)、(X8,AB1)、(X8,AB2)、(X8,AB3)、(X8,AB4)、(X8,AB5)、(X8,AB6)、(X8,AB7)、(X8,AB8)、(X8,AB9)、(X8,AB10)、(X8,AB11)、(X8,AB12)、(X8,AB13)、(X9,AB1)、(X9,AB2)、(X9,AB3)、(X9,AB4)、(X9,AB5)、(X9,AB6)、(X9,AB7)、(X9,AB8)、(X9,AB9)、(X9,AB10)、(X9,AB11)、(X9,AB12)、(X9,AB13)、(X10,AB1)、(X10,AB2)、(X10,AB3)、(X10,AB4)、(X10,AB5)、(X10,AB6)、(X10,AB7)、(X10,AB8)、(X10,AB9)、(X10,AB10)、(X10,AB11)、(X10,AB12)、(X10,AB13)、(X11,AB1)、(X11,AB2)、(X11,AB3)、(X11,AB4)、(X11,AB5)、(X11,AB6)、(X11,AB7)、(X11,AB8)、(X11,AB9)、(X11,AB10)、(X11,AB11)、(X11,AB12)、(X11,AB13)、(X12,AB1)、(X12,AB2)、(X12,AB3)、(X12,AB4)、(X12,AB5)、(X12,AB6)、(X12,AB7)、(X12,AB8)、(X12,AB9)、(X12,AB10)、(X12,AB11)、(X12,AB12)、(X12,AB13)、(X13,AB1)、(X13,AB2)、(X13,AB3)、(X13,AB4)、(X13,AB5)、(X13,AB6)、(X13,AB7)、(X13,AB8)、(X13,AB9)、 (X13,AB10)、(X13,AB11)、(X13,AB12)、(X13,AB13)、(X14,AB1)、(X14,AB2)、(X14,AB3)、(X14,AB4)、(X14,AB5)、(X14,AB6)、(X14,AB7)、(X14,AB8)、(X14,AB9)、(X14,AB10)、(X14,AB11)、(X14,AB12)、(X14,AB13)、(X15,AB1)、(X15,AB2)、(X15,AB3)、(X15,AB4)、(X15,AB5)、(X15,AB6)、(X15,AB7)、(X15,AB8)、(X15,AB9)、(X15,AB10)、(X15,AB11)、(X15,AB12)、(X15,AB13)、(X16,AB1)、(X16,AB2)、(X16,AB3)、(X16,AB4)、(X16,AB5)、(X16,AB6)、(X16,AB7)、(X16,AB8)、(X16,AB9)、(X16,AB10)、(X16,AB11)、(X16,AB12)、(X16,AB13)、(X17,AB1)、(X17,AB2)、(X17,AB3)、(X17,AB4)、(X17,AB5)、(X17,AB6)、(X17,AB7)、(X17,AB8)、(X17,AB9)、(X17,AB10)、(X17,AB11)、(X17,AB12)、(X17,AB13)、(X18,AB1)、(X18,AB2)、(X18,AB3)、(X18,AB4)、(X18,AB5)、(X18,AB6)、(X18,AB7)、(X18,AB8)、(X18,AB9)、(X18,AB10)、(X18,AB11)、(X18,AB12)、(X18,AB13)、(X19,AB1)、(X19,AB2)、(X19,AB3)、(X19,AB4)、(X19,AB5)、(X19,AB6)、(X19,AB7)、(X19,AB8)、(X19,AB9)、(X19,AB10)、(X19,AB11)、(X19,AB12)、(X19,AB13)、(X20,AB1)、(X20,AB2)、(X20,AB3)、(X20,AB4)、(X20,AB5)、(X20,AB6)、(X20,AB7)、(X20,AB8)、(X20,AB9)、(X20,AB10)、(X20,AB11)、(X20,AB12)、(X20,AB13)、(X21,AB1)、(X21,AB2)、(X21,AB3)、(X21,AB4)、(X21,AB5)、(X21,AB6)、(X21,AB7)、(X21,AB8)、(X21,AB9)、(X21,AB10)、(X21,AB11)、(X21,AB12)、(X21,AB13)、(X22,AB1)、(X22,AB2)、(X22,AB3)、(X22,AB4)、(X22,AB5)、(X22,AB6)、(X22,AB7)、(X22,AB8)、(X22,AB9)、(X22,AB10)、(X22,AB11)、(X22,AB12)、(X22,AB13)、(X23,AB1)、(X23,AB2)、(X23,AB3)、(X23,AB4)、(X23,AB5)、(X23,AB6)、(X23,AB7)、(X23,AB8)、(X23,AB9)、 (X23,AB10)、(X23,AB11)、(X23,AB12)、(X23,AB13)、(X24,AB1)、(X24,AB2)、(X24,AB3)、(X24,AB4)、(X24,AB5)、(X24,AB6)、(X24,AB7)、(X24,AB8)、(X24,AB9)、(X24,AB10)、(X24,AB11)、(X24,AB12)、(X24,AB13)、(X25,AB1)、(X25,AB2)、(X25,AB3)、(X25,AB4)、(X25,AB5)、(X25,AB6)、(X25,AB7)、(X25,AB8)、(X25,AB9)、(X25,AB10)、(X25,AB11)、(X25,AB12)、(X25,AB13)、(X26,AB1)、(X26,AB2)、(X26,AB3)、(X26,AB4)、(X26,AB5)、(X26,AB6)、(X26,AB7)、(X26,AB8)、(X26,AB9)、(X26,AB10)、(X26,AB11)、(X26,AB12)、(X26,AB13)、(X27,AB1)、(X27,AB2)、(X27,AB3)、(X27,AB4)、(X27,AB5)、(X27,AB6)、(X27,AB7)、(X27,AB8)、(X27,AB9)、(X27,AB10)、(X27,AB11)、(X27,AB12)、(X27,AB13)、(X28,AB1)、(X28,AB2)、(X28,AB3)、(X28,AB4)、(X28,AB5)、(X28,AB6)、(X28,AB7)、(X28,AB8)、(X28,AB9)、(X28,AB10)、(X28,AB11)、(X28,AB12)、(X28,AB13)、(X29,AB1)、(X29,AB2)、(X29,AB3)、(X29,AB4)、(X29,AB5)、(X29,AB6)、(X29,AB7)、(X29,AB8)、(X29,AB9)、(X29,AB10)、(X29,AB11)、(X29,AB12)、(X29,AB13)、(X30,AB1)、(X30,AB2)、(X30,AB3)、(X30,AB4)、(X30,AB5)、(X30,AB6)、(X30,AB7)、(X30,AB8)、(X30,AB9)、(X30,AB10)、(X30,AB11)、(X30,AB12)、(X30,AB13)、(X31,AB1)、(X31,AB2)、(X31,AB3)、(X31,AB4)、(X31,AB5)、(X31,AB6)、(X31,AB7)、(X31,AB8)、(X31,AB9)、(X31,AB10)、(X31,AB11)、(X31,AB12)、(X31,AB13)、(X32,AB1)、(X32,AB2)、(X32,AB3)、(X32,AB4)、(X32,AB5)、(X32,AB6)、(X32,AB7)、(X32,AB8)、(X32,AB9)、(X32,AB10)、(X32,AB11)、(X32,AB12)、(X32,AB13)、(X33,AB1)、(X33,AB2)、(X33,AB3)、(X33,AB4)、(X33,AB5)、(X33,AB6)、(X33,AB7)、(X33,AB8)、(X33,AB9)、 (X33,AB10)、(X33,AB11)、(X33,AB12)、(X33,AB13)、(X34,AB1)、(X34,AB2)、(X34,AB3)、(X34,AB4)、(X34,AB5)、(X34,AB6)、(X34,AB7)、(X34,AB8)、(X34,AB9)、(X34,AB10)、(X34,AB11)、(X34,AB12)、(X34,AB13)、(X35,AB1)、(X35,AB2)、(X35,AB3)、(X35,AB4)、(X35,AB5)、(X35,AB6)、(X35,AB7)、(X35,AB8)、(X35,AB9)、(X35,AB10)、(X35,AB11)、(X35,AB12)、(X35,AB13)、(X36,AB1)、(X36,AB2)、(X36,AB3)、(X36,AB4)、(X36,AB5)、(X36,AB6)、(X36,AB7)、(X36,AB8)、(X36,AB9)、(X36,AB10)、(X36,AB11)、(X36,AB12)、(X36,AB13)、(X37,AB1)、(X37,AB2)、(X37,AB3)、(X37,AB4)、(X37,AB5)、(X37,AB6)、(X37,AB7)、(X37,AB8)、(X37,AB9)、(X37,AB10)、(X37,AB11)、(X37,AB12)、(X37,AB13)、(X38,AB1)、(X38,AB2)、(X38,AB3)、(X38,AB4)、(X38,AB5)、(X38,AB6)、(X38,AB7)、(X38,AB8)、(X38,AB9)、(X38,AB10)、(X38,AB11)、(X38,AB12)、(X38,AB13)、(X39,AB1)、(X39,AB2)、(X39,AB3)、(X39,AB4)、(X39,AB5)、(X39,AB6)、(X39,AB7)、(X39,AB8)、(X39,AB9)、(X39,AB10)、(X39,AB11)、(X39,AB12)、(X39,AB13)、(X40,AB1)、(X40,AB2)、(X40,AB3)、(X40,AB4)、(X40,AB5)、(X40,AB6)、(X40,AB7)、(X40,AB8)、(X40,AB9)、(X40,AB10)、(X40,AB11)、(X40,AB12)、(X40,AB13)、(X41,AB1)、(X41,AB2)、(X41,AB3)、(X41,AB4)、(X41,AB5)、(X41,AB6)、(X41,AB7)、(X41,AB8)、(X41,AB9)、(X41,AB10)、(X41,AB11)、(X41,AB12)、(X41,AB13)、(X42,AB1)、(X42,AB2)、(X42,AB3)、(X42,AB4)、(X42,AB5)、(X42,AB6)、(X42,AB7)、(X42,AB8)、(X42,AB9)、(X42,AB10)、(X42,AB11)、(X42,AB12)、(X42,AB13)、(X43,AB1)、(X43,AB2)、(X43,AB3)、(X43,AB4)、(X43,AB5)、(X43,AB6)、(X43,AB7)、(X43,AB8)、(X43,AB9)、 (X43,AB10)、(X43,AB11)、(X43,AB12)、(X43,AB13)、(X44,AB1)、(X44,AB2)、(X44,AB3)、(X44,AB4)、(X44,AB5)、(X44,AB6)、(X44,AB7)、(X44,AB8)、(X44,AB9)、(X44,AB10)、(X44,AB11)、(X44,AB12)、(X44,AB13)、(X45,AB1)、(X45,AB2)、(X45,AB3)、(X45,AB4)、(X45,AB5)、(X45,AB6)、(X45,AB7)、(X45,AB8)、(X45,AB9)、(X45,AB10)、(X45,AB11)、(X45,AB12)、(X45,AB13)、(X46,AB1)、(X46,AB2)、(X46,AB3)、(X46,AB4)、(X46,AB5)、(X46,AB6)、(X46,AB7)、(X46,AB8)、(X46,AB9)、(X46,AB10)、(X46,AB11)、(X46,AB12)、(X46,AB13)、(X47,AB1)、(X47,AB2)、(X47,AB3)、(X47,AB4)、(X47,AB5)、(X47,AB6)、(X47,AB7)、(X47,AB8)、(X47,AB9)、(X47,AB10)、(X47,AB11)、(X47,AB12)、(X47,AB13)、(X48,AB1)、(X48,AB2)、(X48,AB3)、(X48,AB4)、(X48,AB5)、(X48,AB6)、(X48,AB7)、(X48,AB8)、(X48,AB9)、(X48,AB10)、(X48,AB11)、(X48,AB12)或(X48,AB13)。 R 3b is an alkyl group, n is 2, R 5 is a halogen, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X47), X is -S- or -O-, and R 3a is H or an alkyl group. R 3b is H, and R 2a and R 2b together with the carbon atom to which they are attached may form a cycloalkane substituted with 1 or 2 halogens, and R 1 is an alkyl group or a haloalkyl group (hereinafter referred to as X48), a ring A is substituted or unsubstituted benzene and ring B is substituted or unsubstituted pyridine (hereinafter referred to as AB1), ring A is substituted or unsubstituted benzene and ring B is substituted or not Substituted pyr (hereinafter referred to as AB2), ring A is substituted or unsubstituted benzene and ring B is substituted or unsubstituted An azole (hereinafter referred to as AB3), ring A is a substituted or unsubstituted benzene and ring B is a substituted or unsubstituted pyrimidine or a substituted or unsubstituted fluorene (hereinafter referred to as AB4), ring A is a substituted or unsubstituted pyridine, and ring B is a substituted or unsubstituted pyridine (hereinafter referred to as AB5), and ring A is substituted or unsubstituted. Pyridine, and ring B is substituted or unsubstituted pyridyl (hereinafter referred to as AB6), ring A is a substituted or unsubstituted pyridine, and ring B is substituted or unsubstituted An azole (hereinafter referred to as AB7), ring A is a benzene substituted with a halogen such as F or Cl, and ring B is one or two selected from the group consisting of halogen, cyano, alkyl, alkoxy and haloalkoxy. a substituent-substituted pyridine (hereinafter referred to as AB8), ring A is a benzene substituted with a halogen such as F or Cl, and ring B is one or two selected from haloalkyl, alkoxy, haloalkoxy Pyridyl substituted with substituents of alkynyl, alkynyloxy and cycloalkylalkoxy (hereinafter referred to as AB9), ring A is a benzene substituted with a halogen such as F or Cl, and ring B is substituted with one or two substituents selected from an alkyl group and a haloalkyl group. An azole (hereinafter referred to as AB10), ring A is a benzene substituted with a halogen such as F or Cl, and ring B is a pyrimidine substituted with one or two substituents selected from a haloalkoxy group or one or two Substituted by a substituent selected from an alkoxy group (hereinafter referred to as AB11), ring A is a halogen-substituted pyridine and ring B is a pyridine (hereinafter referred to as AB12) substituted with one or two substituents selected from a halogen and a cyano group, and ring A is a halogen. Substituted pyridine and ring B is pyridyl substituted with one or two substituents selected from alkoxy and haloalkoxy (hereinafter referred to as AB13). Examples of the combination of "X, R 3a , R 3b , R 2a , R 2b and R 1 " and "ring A and ring B" (X, AB) of the compound of the formula (I) are as follows: (X1, AB1), X1, AB2), (X1, AB3), (X1, AB4), (X1, AB5), (X1, AB6), (X1, AB7), (X1, AB8), (X1, AB9), (X1, AB10), (X1, AB11), (X1, AB12), (X1, AB13), (X2, AB1), (X2, AB2), (X2, AB3), (X2, AB4), (X2, AB5) , (X2, AB6), (X2, AB7), (X2, AB8), (X2, AB9), (X2, AB10), (X2, AB11), (X2, AB12), (X2, AB13), ( X3, AB1), (X3, AB2), (X3, AB3), (X3, AB4), (X3, AB5), (X3, AB6), (X3, AB7), (X3, AB8), (X3, AB9), (X3, AB10), (X3, AB11), (X3, AB12), (X3, AB13), (X4, AB1), (X4, AB2), (X4, AB3), (X4, AB4) , (X4, AB5), (X4, AB6), (X4, AB7), (X4, AB8), (X4, AB9), (X4, AB10), (X4, AB11), (X4, AB12), ( X4, AB13), (X5, AB1), (X5, AB2), (X5, AB3), (X5, AB4), (X5, AB5), (X5, AB6), (X5, AB7), (X5, AB8), (X5, AB9), (X5, AB10), (X5, AB11), (X5, AB12), (X5, AB13), (X6, AB1), (X6, AB2), (X6, AB3) , (X6, AB4), (X6, AB5), (X6, AB6), (X6, AB7), (X6, AB8), (X6, AB9), (X6, AB10), (X6, AB11), ( X6, AB12), (X6, AB13), ( X7, AB1), (X7, AB2), (X7, AB3), (X7, AB4), (X7, AB5), (X7, AB6), (X7, AB7), (X7, AB8), (X7, AB9), (X7, AB10), (X7, AB11), (X7, AB12), (X7, AB13), (X8, AB1), (X8, AB2), (X8, AB3), (X8, AB4) , (X8, AB5), (X8, AB6), (X8, AB7), (X8, AB8), (X8, AB9), (X8, AB10), (X8, AB11), (X8, AB12), ( X8, AB13), (X9, AB1), (X9, AB2), (X9, AB3), (X9, AB4), (X9, AB5), (X9, AB6), (X9, AB7), (X9, AB8), (X9, AB9), (X9, AB10), (X9, AB11), (X9, AB12), (X9, AB13), (X10, AB1), (X10, AB2), (X10, AB3) , (X10, AB4), (X10, AB5), (X10, AB6), (X10, AB7), (X10, AB8), (X10, AB9), (X10, AB10), (X10, AB11), ( X10, AB12), (X10, AB13), (X11, AB1), (X11, AB2), (X11, AB3), (X11, AB4), (X11, AB5), (X11, AB6), (X11, AB7), (X11, AB8), (X11, AB9), (X11, AB10), (X11, AB11), (X11, AB12), (X11, AB13), (X12, AB1), (X12, AB2) , (X12, AB3), (X12, AB4), (X12, AB5), (X12, AB6), (X12, AB7), (X12, AB8), (X12, AB9), (X12, AB10), ( X12, AB11), (X12, AB12), (X12, AB13), (X13, AB1), (X13, AB2), (X13, AB3), (X13, AB4), (X13, AB5), (X13, AB6), (X13, AB7 ), (X13, AB8), (X13, AB9), (X13, AB10), (X13, AB11), (X13, AB12), (X13, AB13), (X14, AB1), (X14, AB2), (X14, AB3), (X14, AB4), (X14, AB5), (X14, AB6), (X14, AB7), (X14, AB8), (X14, AB9), (X14, AB10), (X14 , AB11), (X14, AB12), (X14, AB13), (X15, AB1), (X15, AB2), (X15, AB3), (X15, AB4), (X15, AB5), (X15, AB6 ), (X15, AB7), (X15, AB8), (X15, AB9), (X15, AB10), (X15, AB11), (X15, AB12), (X15, AB13), (X16, AB1), (X16, AB2), (X16, AB3), (X16, AB4), (X16, AB5), (X16, AB6), (X16, AB7), (X16, AB8), (X16, AB9), (X16) , AB10), (X16, AB11), (X16, AB12), (X16, AB13), (X17, AB1), (X17, AB2), (X17, AB3), (X17, AB4), (X17, AB5 ), (X17, AB6), (X17, AB7), (X17, AB8), (X17, AB9), (X17, AB10), (X17, AB11), (X17, AB12), (X17, AB13), (X18, AB1), (X18, AB2), (X18, AB3), (X18, AB4), (X18, AB5), (X18, AB6), (X18, AB7), (X18, AB8), (X18 , AB9), (X18, AB10), (X18, AB11), (X18, AB12), (X18, AB13), (X19, AB1), (X19, AB2), (X19, AB3), (X19, AB4 ), (X19, AB5), (X19, AB6), (X19, AB7), (X19, AB8), (X19, AB9), (X19, AB10) (X19, AB11), (X19, AB12), (X19, AB13), (X20, AB1), (X20, AB2), (X20, AB3), (X20, AB4), (X20, AB5), (X20) , AB6), (X20, AB7), (X20, AB8), (X20, AB9), (X20, AB10), (X20, AB11), (X20, AB12), (X20, AB13), (X21, AB1 ), (X21, AB2), (X21, AB3), (X21, AB4), (X21, AB5), (X21, AB6), (X21, AB7), (X21, AB8), (X21, AB9), (X21, AB10), (X21, AB11), (X21, AB12), (X21, AB13), (X22, AB1), (X22, AB2), (X22, AB3), (X22, AB4), (X22) , AB5), (X22, AB6), (X22, AB7), (X22, AB8), (X22, AB9), (X22, AB10), (X22, AB11), (X22, AB12), (X22, AB13 ), (X23, AB1), (X23, AB2), (X23, AB3), (X23, AB4), (X23, AB5), (X23, AB6), (X23, AB7), (X23, AB8), (X23, AB9), (X23, AB10), (X23, AB11), (X23, AB12), (X23, AB13), (X24, AB1), (X24, AB2), (X24, AB3), (X24) , AB4), (X24, AB5), (X24, AB6), (X24, AB7), (X24, AB8), (X24, AB9), (X24, AB10), (X24, AB11), (X24, AB12 ), (X24, AB13), (X25, AB1), (X25, AB2), (X25, AB3), (X25, AB4), (X25, AB5), (X25, AB6), (X25, AB7), (X25, AB8), (X25, AB9), (X25, AB10), (X25, AB11), (X25, AB12), (X25, AB13) (X26, AB1), (X26, AB2), (X26, AB3), (X26, AB4), (X26, AB5), (X26, AB6), (X26, AB7), (X26, AB8), (X26 , AB9), (X26, AB10), (X26, AB11), (X26, AB12), (X26, AB13), (X27, AB1), (X27, AB2), (X27, AB3), (X27, AB4 ), (X27, AB5), (X27, AB6), (X27, AB7), (X27, AB8), (X27, AB9), (X27, AB10), (X27, AB11), (X27, AB12), (X27, AB13), (X28, AB1), (X28, AB2), (X28, AB3), (X28, AB4), (X28, AB5), (X28, AB6), (X28, AB7), (X28 , AB8), (X28, AB9), (X28, AB10), (X28, AB11), (X28, AB12), (X28, AB13), (X29, AB1), (X29, AB2), (X29, AB3 ), (X29, AB4), (X29, AB5), (X29, AB6), (X29, AB7), (X29, AB8), (X29, AB9), (X29, AB10), (X29, AB11), (X29, AB12), (X29, AB13), (X30, AB1), (X30, AB2), (X30, AB3), (X30, AB4), (X30, AB5), (X30, AB6), (X30) , AB7), (X30, AB8), (X30, AB9), (X30, AB10), (X30, AB11), (X30, AB12), (X30, AB13), (X31, AB1), (X31, AB2 ), (X31, AB3), (X31, AB4), (X31, AB5), (X31, AB6), (X31, AB7), (X31, AB8), (X31, AB9), (X31, AB10), (X31, AB11), (X31, AB12), (X31, AB13), (X32, AB1), (X32, AB2), (X32, AB3), (X 32, AB4), (X32, AB5), (X32, AB6), (X32, AB7), (X32, AB8), (X32, AB9), (X32, AB10), (X32, AB11), (X32, AB12), (X32, AB13), (X33, AB1), (X33, AB2), (X33, AB3), (X33, AB4), (X33, AB5), (X33, AB6), (X33, AB7) , (X33, AB8), (X33, AB9), (X33, AB10), (X33, AB11), (X33, AB12), (X33, AB13), (X34, AB1), (X34, AB2), ( X34, AB3), (X34, AB4), (X34, AB5), (X34, AB6), (X34, AB7), (X34, AB8), (X34, AB9), (X34, AB10), (X34, AB11), (X34, AB12), (X34, AB13), (X35, AB1), (X35, AB2), (X35, AB3), (X35, AB4), (X35, AB5), (X35, AB6) , (X35, AB7), (X35, AB8), (X35, AB9), (X35, AB10), (X35, AB11), (X35, AB12), (X35, AB13), (X36, AB1), ( X36, AB2), (X36, AB3), (X36, AB4), (X36, AB5), (X36, AB6), (X36, AB7), (X36, AB8), (X36, AB9), (X36, AB10), (X36, AB11), (X36, AB12), (X36, AB13), (X37, AB1), (X37, AB2), (X37, AB3), (X37, AB4), (X37, AB5) , (X37, AB6), (X37, AB7), (X37, AB8), (X37, AB9), (X37, AB10), (X37, AB11), (X37, AB12), (X37, AB13), ( X38, AB1), (X38, AB2), (X38, AB3), (X38, AB4), (X38, AB5), (X38, AB6), (X38, AB7), (X38, AB8), (X38, AB9), (X38, AB10), (X38, AB11), (X38, AB12), (X38, AB13), (X39, AB1), (X39, AB2) , (X39, AB3), (X39, AB4), (X39, AB5), (X39, AB6), (X39, AB7), (X39, AB8), (X39, AB9), (X39, AB10), ( X39, AB11), (X39, AB12), (X39, AB13), (X40, AB1), (X40, AB2), (X40, AB3), (X40, AB4), (X40, AB5), (X40, AB6), (X40, AB7), (X40, AB8), (X40, AB9), (X40, AB10), (X40, AB11), (X40, AB12), (X40, AB13), (X41, AB1) , (X41, AB2), (X41, AB3), (X41, AB4), (X41, AB5), (X41, AB6), (X41, AB7), (X41, AB8), (X41, AB9), ( X41, AB10), (X41, AB11), (X41, AB12), (X41, AB13), (X42, AB1), (X42, AB2), (X42, AB3), (X42, AB4), (X42, AB5), (X42, AB6), (X42, AB7), (X42, AB8), (X42, AB9), (X42, AB10), (X42, AB11), (X42, AB12), (X42, AB13) , (X43, AB1), (X43, AB2), (X43, AB3), (X43, AB4), (X43, AB5), (X43, AB6), (X43, AB7), (X43, AB8), ( X43, AB9), (X43, AB10), (X43, AB11), (X43, AB12), (X43, AB13), (X44, AB1), (X44, AB2), (X44, AB3), (X44, AB4), (X44, AB5), (X44, AB6), (X44, AB7), (X44, AB8), (X44, AB9), (X44, AB1 0), (X44, AB11), (X44, AB12), (X44, AB13), (X45, AB1), (X45, AB2), (X45, AB3), (X45, AB4), (X45, AB5) , (X45, AB6), (X45, AB7), (X45, AB8), (X45, AB9), (X45, AB10), (X45, AB11), (X45, AB12), (X45, AB13), ( X46, AB1), (X46, AB2), (X46, AB3), (X46, AB4), (X46, AB5), (X46, AB6), (X46, AB7), (X46, AB8), (X46, AB9), (X46, AB10), (X46, AB11), (X46, AB12), (X46, AB13), (X47, AB1), (X47, AB2), (X47, AB3), (X47, AB4) , (X47, AB5), (X47, AB6), (X47, AB7), (X47, AB8), (X47, AB9), (X47, AB10), (X47, AB11), (X47, AB12), ( X47, AB13), (X48, AB1), (X48, AB2), (X48, AB3), (X48, AB4), (X48, AB5), (X48, AB6), (X48, AB7), (X48, AB8), (X48, AB9), (X48, AB10), (X48, AB11), (X48, AB12) or (X48, AB13).

式(I)化合物不限於特定異構體，且包括所有可能的異構體，諸如酮-烯醇異構體、亞胺-烯胺異構體、非對映異構體、光學異構體及旋轉異構體、外消旋體及其混合物。舉例而言，式(I)化合物包括以下互變異構體。 The compound of the formula (I) is not limited to a specific isomer, and includes all possible isomers such as a keto-enol isomer, an imine-enamine isomer, a diastereomer, an optical isomer. And rotamers, racemates and mixtures thereof. For example, the compounds of formula (I) include the following tautomers.

式(I)化合物具有不對稱碳原子且該化合物包括以下光學異構體。 The compound of formula (I) has an asymmetric carbon atom and the compound includes the following optical isomers.

在一個實施例中，本發明化合物為如下： In one embodiment, the compounds of the invention are as follows:

光學活性式(I)化合物可藉由採用光學活性起始物質、藉由在適合之階段之不對稱性合成獲得光學活性中間物或藉由在適合之階段進行中間物或目標化合物(其中之每一者為外消旋體)之光學解析度產生。用於光學解析之方法之實例為使用光學活性管柱分離光學異構體；使用酶促反應之動態光學解析；藉由使用對掌性酸或對掌性鹼之鹽形成的非對映異構體之結晶解析；及較佳結晶方法。 The optically active compound of the formula (I) can be obtained by using an optically active starting material, obtaining an optically active intermediate by asymmetric synthesis at a suitable stage or by carrying out an intermediate or a target compound at a suitable stage (each of which One is the optical resolution of the racemic body). An example of a method for optical resolution is the separation of optical isomers using an optically active column; dynamic optical resolution using an enzymatic reaction; by the use of diastereoisomers formed with a palmitic acid or a salt of a palmitic base Crystallization analysis of the body; and preferred crystallization method.

式(I)化合物之一或多個氫、碳及/或其他原子可分別藉由氫、碳及/或其他原子之同位素置換。同位素之實例包括氫、碳、氮、氧、磷、硫、氟、碘及氯之同位素，諸如分別地，2H、3H、11C、13C、14C、15N、18O、17O、31P、32P、35S、18F、123I及36Cl。式(I)化合物亦包括藉由此類同位素置換之化合物。藉由此類同位素置換之化合物亦適用作藥物，且包括式(I)化合物之所有放射性標記化合物。本發明包括用於製造「放射性標記化合物」之「放射性標記方法」且該方法適用作代謝藥物動力學研究，結合分析及/或診斷中之研究之工具。 One or more of the hydrogen, carbon and/or other atoms of the compound of formula (I) may be replaced by isotopes of hydrogen, carbon and/or other atoms, respectively. Examples of isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 respectively. O, 31 P, 32 P, 35 S, 18 F, 123 I and 36 Cl. Compounds of formula (I) also include compounds substituted by such isotopes. Compounds substituted by such isotopes are also suitable as medicaments and include all radiolabeled compounds of the compounds of formula (I). The present invention includes a "radiolabeling method" for the manufacture of "radiolabeled compounds" and is useful as a tool for metabolic pharmacokinetic studies in conjunction with studies in analysis and/or diagnostics.

式(I)化合物之放射性標記化合物可藉由此項技術中已知之方法 製備。舉例而言，氚化式(I)化合物可藉由將氚引入特定式(I)化合物中，諸如藉由用氚催化脫鹵而製備。此方法可包括在諸如Pd/C之適合之催化劑存在下，在存在或不存在鹼之情況下使式(I)化合物之適當鹵化前驅體與氚氣反應。製備氚化化合物之其他適合之方法可見於Isotopes in the Physical and Biomedical Sciences，第1卷，Labeled Compounds(部分A)，第6章(1987)中。14C標記之化合物可藉由採用具有14C碳之起始物質製備。 Radiolabeled compounds of the compounds of formula (I) can be prepared by methods known in the art. For example, deuterated compounds of formula (I) can be prepared by introducing hydrazine into a particular compound of formula (I), such as by catalytic dehalogenation with hydrazine. This process can include reacting a suitable halogenated precursor of the compound of formula (I) with helium in the presence or absence of a base in the presence of a suitable catalyst such as Pd/C. Other suitable methods for preparing deuterated compounds can be found in Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). The 14 C-labeled compound can be prepared by using a starting material having a 14 C carbon.

作為式(I)化合物之醫藥學上可接受之鹽，實例包括與鹼金屬(例如鋰、鈉及鉀)、鹼土金屬(例如鈣及鋇)、鎂、過渡金屬(例如鋅及鐵)、氨、有機鹼(例如三甲胺、三乙胺、二環己胺、乙醇胺、二乙醇胺、三乙醇胺、葡甲胺、二乙醇胺、乙二胺、吡啶、甲吡啶、喹啉)及胺基酸之鹽，及與無機酸(例如氫氯酸、硫酸、硝酸、碳酸、氫溴酸、磷酸及氫碘酸)及有機酸(例如甲酸、乙酸、丙酸、三氟乙酸、檸檬酸、乳酸、酒石酸、草酸、順丁烯二酸、反丁烯二酸、杏仁酸、戊二酸、蘋果酸、苯甲酸、鄰苯二甲酸、抗壞血酸、苯磺酸、對甲苯磺酸、甲磺酸及乙磺酸)之鹽。特定實例為與氫氯酸、硫酸、磷酸、酒石酸或甲磺酸之鹽。此等鹽可由常用方法形成。 As the pharmaceutically acceptable salt of the compound of the formula (I), examples include alkali metals (for example, lithium, sodium and potassium), alkaline earth metals (for example, calcium and barium), magnesium, transition metals (for example, zinc and iron), and ammonia. , organic bases (such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, pyridinium, quinoline) and salts of amino acids And with inorganic acids (such as hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid and hydroiodic acid) and organic acids (such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, Oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid and ethanesulfonic acid ) the salt. A specific example is a salt with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid or methanesulfonic acid. These salts can be formed by conventional methods.

由式(I)代表之本發明化合物或其醫藥學上可接受之鹽可形成溶劑合物(例如水合物等)及/或晶體多晶型物。本發明涵蓋彼等各種溶劑合物及晶體多晶型物。「溶劑合物」可為其中任何數目之溶劑分子(例如水分子等)與由式(I)代表之化合物配位之彼等者。當允許由式(I)代表之化合物或其醫藥學上可接受之鹽在大氣中靜置時，化合物可吸收水，導致吸附水之附接或形成水合物。由式(I)代表之化合物或其醫藥學上可接受之鹽之再結晶可產生晶體多晶型物。 The compound of the present invention represented by the formula (I) or a pharmaceutically acceptable salt thereof can form a solvate (e.g., hydrate or the like) and/or a crystal polymorph. The present invention encompasses various solvates and crystalline polymorphs thereof. A "solvate" may be one in which any number of solvent molecules (e.g., water molecules, etc.) are coordinated to a compound represented by formula (I). When the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is allowed to stand in the atmosphere, the compound can absorb water, resulting in adsorption of water or formation of a hydrate. Recrystallization of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof can produce a crystalline polymorph.

由式(I)代表之本發明化合物或其醫藥學上可接受之鹽可形成前藥。本發明亦涵蓋該等各種前藥。前藥為本發明化合物之衍生物，其 具有化學或代謝可降解基團，且為經由溶劑分解或在生理條件下在活體內轉化為本發明之醫藥學活性化合物之化合物。前藥包括在生理條件下在活體內經由酶促氧化、還原、水解及其類似者轉化為由式(I)代表之化合物的化合物及藉由胃酸及其類似者經由水解轉化為由式(I)代表之化合物的化合物。選擇及製備適合之前藥衍生物之方法例如描述於Design of Prodrugs,Elsevier,Amsterdam 1985中。前藥本身可為活性化合物。 The compound of the present invention represented by the formula (I) or a pharmaceutically acceptable salt thereof can form a prodrug. The invention also covers such various prodrugs. Prodrug derivatives of the compounds of the present invention, which has a chemically or metabolically degradable group, and the decomposition of the present compound, or a pharmaceutically active compound of the invention under physiological conditions in vivo via conversion solvent. Prodrugs include compounds which are converted to a compound represented by formula (I) by enzymatic oxidation, reduction, hydrolysis and the like in physiological conditions under physiological conditions and are converted into the formula (I by hydrolysis) by gastric acid and the like. a compound representing a compound. Methods for the selection and preparation of suitable drug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. The prodrug itself can be the active compound.

當式(I)化合物或其醫藥學上可接受之鹽具有羥基時，前藥包括醯氧基衍生物及磺醯基氧基衍生物，其可藉由使具有羥基之化合物與適合之酸鹵化物、適合之酸酐、適合之磺醯氯、適合之磺醯酸酐及混合酸酐或與縮合劑反應製備。實例為CH3COO-、C2H5COO-、t-BuCOO-、C15H31COO-、PhCOO-、(m-NaOOCPh)COO-、NaOOCCH2CH2COO-、CH3CH(NH2)COO-、CH2N(CH3)2COO-、CH3SO3-、CH3CH2SO3-、CF3SO3-、CH2FSO3-、CF3CH2SO3-、p-CH3-O-PhSO3-、PhSO3-及p-CH3PhSO3-。 When the compound of the formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group, the prodrug includes a decyloxy derivative and a sulfonyloxy derivative which can be halogenated by reacting a compound having a hydroxyl group with a suitable acid Preparation, suitable anhydride, suitable sulfonium chloride, suitable sulfonate anhydride and mixed anhydride or reacted with a condensing agent. Examples are CH 3 COO-, C 2 H 5 COO-, t-BuCOO-, C 15 H 31 COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH 2 CH 2 COO-, CH 3 CH (NH 2 COO-, CH 2 N(CH 3 ) 2 COO-, CH 3 SO 3 -, CH 3 CH 2 SO 3 -, CF 3 SO 3 -, CH 2 FSO 3 -, CF 3 CH 2 SO 3 -, p -CH 3 -O-PhSO 3 -, PhSO 3 - and p-CH 3 PhSO 3 -.

式(I)化合物可藉由下文所述之方法，連同熟習此項技術者已知之合成方法製備。 Compounds of formula (I) can be prepared by methods described below, in conjunction with synthetic methods known to those skilled in the art.

起始物質為市售的或可根據已知方法製備。 The starting materials are either commercially available or can be prepared according to known methods.

在以下合成中之任一者期間，可能需要或較佳保護任一分子上之敏感或反應性基團。在該情況下，此等保護可藉助於習知保護基，諸如Greene's Protective Group in Organic Synthesis,John Wily & Sons,2007中所述之彼等保護基達成。 Sensitive or reactive groups on either molecule may be required or preferably protected during any of the following syntheses. In this case, such protection can be achieved by means of conventional protecting groups such as those described in Greene's Protective Group in Organic Synthesis, John Wily & Sons, 2007.

熟習此項技術者應瞭解，下文所述之化合物將產生非對映異構體及/或對映異構體之混合物，其可使用諸如結晶、矽膠層析、對掌性或非對掌性高效液相層析(HPLC)及對掌性超臨界流體(SFC)層析之習知技術在以下程序之相關階段分離，得到本發明之單一對映異構 體。 Those skilled in the art will appreciate that the compounds described below will result in a mixture of diastereomers and/or enantiomers which may be used, for example, by crystallization, gelatin chromatography, palmar or non-palm High performance liquid chromatography (HPLC) and conventional techniques for palmitic supercritical fluid (SFC) chromatography are separated at relevant stages of the following procedures to provide a single enantiomer of the invention body.

在所有以下步驟期間，可恰當改變待進行之步驟之次序。在各步驟中，可分離中間物，接著用於下一步驟中。反應時間、反應溫度、溶劑、試劑、保護基等所有者僅為範例且不受限，只要其不對反應產生不良影響。 The order of the steps to be performed can be appropriately changed during all of the following steps. In each step, the intermediate can be separated and used in the next step. The owner of the reaction time, the reaction temperature, the solvent, the reagent, the protecting group, and the like are merely examples and are not limited as long as they do not adversely affect the reaction.

一般程序A： General procedure A:

其中P1為烷基，P2中之每一者為氫或保護基，諸如烷基、苯甲醯基、苯甲基、4-甲氧基苯甲基或2,4-二甲氧基苯甲基，Y為鹵素(例如Br、I)、硝基或三氟乙醯基胺基(-NHCOCF3)，且其他符號與上文所定義相同。 Wherein P 1 is an alkyl group, and each of P 2 is hydrogen or a protecting group such as an alkyl group, a benzhydryl group, a benzyl group, a 4-methoxybenzyl group or a 2,4-dimethoxy group. Benzyl, Y is halogen (eg Br, I), nitro or trifluoroethylamino (-NHCOCF 3 ), and the other symbols are as defined above.

一般程序A為一種經由步驟1至步驟7之多個步驟自式(A1)化合物 製備式(Ia)化合物之方法。熟習此項技術者應瞭解，保護基P1及P2可取決於用於隨後步驟中之反應條件選擇。式(A1)之起始物質可以與Chem.Rev.2010,110,3600-3740中所述之條件類似之方式製備。 General Procedure A is a process for the preparation of a compound of formula (Ia) from a compound of formula (A1) via a plurality of steps from step 1 to step 7. Those skilled in the art will appreciate, the protecting group P 1 and P 2 may be used in subsequent steps depend on the selected reaction conditions. The starting materials of formula (A1) can be prepared in a manner similar to that described in Chem. Rev. 2010, 110, 3600-3740.

步驟1： step 1:

式(A2)化合物可藉由亞磺醯亞胺(A1)與來源於對應酯之烯醇化物之曼尼期反應(Mannich reaction)製備。此類型之反應可使用Chem.Rev.2010,110,3600-3740中所述之條件進行。較佳地，烯醇化物可製備自對應酯、二異丙胺基鋰(LDA)及TiCl(Oi-Pr)3，其可隨後與(A1)反應，得到式(A2)化合物。用於此步驟中之溶劑在其不干擾反應之程度上不受特別限制。溶劑之實例包括四氫呋喃、1,4-二烷、1,2-二甲氧乙烷、***、甲苯及苯。反應溫度較佳為-78℃至-30℃。反應時間不受特別限制且通常為5分鐘至24小時，較佳為30分鐘至24小時。 The compound of the formula (A2) can be produced by a Mannich reaction of a sulfinimide (A1) with an enolate derived from a corresponding ester. This type of reaction can be carried out using the conditions described in Chem. Rev. 2010, 110, 3600-3740. Preferably, the enolate is prepared from the corresponding ester, lithium diisopropylamide (LDA) and TiCl(Oi-Pr) 3 which can be subsequently reacted with (A1) to give a compound of formula (A2). The solvent used in this step is not particularly limited to the extent that it does not interfere with the reaction. Examples of the solvent include tetrahydrofuran, 1,4-two Alkane, 1,2-dimethoxyethane, diethyl ether, toluene and benzene. The reaction temperature is preferably -78 ° C to -30 ° C. The reaction time is not particularly limited and is usually from 5 minutes to 24 hours, preferably from 30 minutes to 24 hours.

步驟2： Step 2:

式(A3)化合物可藉由(A2)之去除保護基製備。此去除保護基反應為熟習此項技術者已知且可在Chem.Rev.2010,110,3600-3740中所述之條件下進行。反應可使用例如氫氯酸在室溫至60℃下於酸性條件下進行。溶劑之實例包括甲醇、1,4-二烷及乙酸乙酯。反應時間不受特別限制且通常為1小時至24小時，較佳為1小時至6小時。 The compound of the formula (A3) can be produced by removing the protective group of (A2). This removal of the protecting group reaction is known to those skilled in the art and can be carried out under the conditions described in Chem. Rev. 2010, 110, 3600-3740. The reaction can be carried out using acidic hydrochloric acid, for example, at room temperature to 60 ° C under acidic conditions. Examples of the solvent include methanol, 1,4-two Alkane and ethyl acetate. The reaction time is not particularly limited and is usually from 1 hour to 24 hours, preferably from 1 hour to 6 hours.

步驟3： Step 3:

式(A4)化合物可藉由(A3)與諸如異硫氰酸苯甲醯酯及異硫氰酸苯甲酯之試劑之反應製備。熟習此項技術者應瞭解，產生自(A3)及諸如二氯硫化碳及硫羰基二咪唑之試劑之異硫氰酸酯可與一級或二級胺反應，獲得式(A4)化合物。用於此步驟中之溶劑在其不干擾反應之程度上不受特別限制。溶劑之實例包括二氯甲烷、四氫呋喃、1,4-二烷、1,2-二甲氧乙烷及甲苯。反應時間不受特別限制且通常為1小時至24小時，較佳為3小時至6小時。反應溫度通常為0℃至60℃，較佳 為0℃至室溫。若用於此步驟中之硫脲形成之試劑可在步驟6中去除保護基，則此等試劑不受特別限制，且較佳試劑為異硫氰酸苯甲醯酯。 The compound of the formula (A4) can be produced by reacting (A3) with a reagent such as benzamidine isothiocyanate and benzyl isothiocyanate. Those skilled in the art will appreciate that isothiocyanates resulting from (A3) and reagents such as carbon dichloride and thiocarbonyldiimidazole can be reacted with a primary or secondary amine to provide a compound of formula (A4). The solvent used in this step is not particularly limited to the extent that it does not interfere with the reaction. Examples of the solvent include dichloromethane, tetrahydrofuran, and 1,4-two. Alkane, 1,2-dimethoxyethane and toluene. The reaction time is not particularly limited and is usually from 1 hour to 24 hours, preferably from 3 hours to 6 hours. The reaction temperature is usually from 0 ° C to 60 ° C, preferably from 0 ° C to room temperature. If the reagent for the formation of thiourea in this step can remove the protecting group in step 6, the reagents are not particularly limited, and the preferred reagent is benzamidine isothiocyanate.

步驟4： Step 4:

式(A5)化合物可藉由(A4)與諸如溴化甲基鎂及溴化乙基鎂之格林納試劑(Grignard reagent)及諸如甲基鋰、丁基鋰及苯基鋰之烷基鋰試劑之反應製備。逐步添加此等親核試劑可允許具有R3a及R3b之各種取代基之式(A5)化合物。所用之溶劑在其不干擾反應之程度上不受特別限制。溶劑之較佳實例包括四氫呋喃、1,4-二烷、1,2-二甲氧乙烷、***、甲苯及苯。反應溫度不受特別限制且通常為5分鐘至24小時，較佳為5分鐘至6小時。反應溫度通常為-100℃至室溫，較佳為-78℃至0℃。 The compound of the formula (A5) can be obtained by (A4) with a Grignard reagent such as methylmagnesium bromide and ethylmagnesium bromide, and an alkyllithium reagent such as methyllithium, butyllithium and phenyllithium. The reaction was prepared. The gradual addition of such nucleophiles allows for compounds of formula (A5) having various substituents of R 3a and R 3b . The solvent used is not particularly limited to the extent that it does not interfere with the reaction. Preferred examples of the solvent include tetrahydrofuran, 1,4-two Alkane, 1,2-dimethoxyethane, diethyl ether, toluene and benzene. The reaction temperature is not particularly limited and is usually from 5 minutes to 24 hours, preferably from 5 minutes to 6 hours. The reaction temperature is usually -100 ° C to room temperature, preferably -78 ° C to 0 ° C.

步驟5： Step 5:

式(A6)化合物可藉由使用諸如m-CPBA、過氧化氫及碳化二亞胺試劑(例如1-乙基-3-(3-二甲胺基丙基)碳化二亞胺)之試劑的(A5)之環化反應製備。或者，式(A6)化合物可藉由(A5)與烷基化試劑反應，繼之以鹼性條件下之環化反應獲得。在前一種情況下，適合之試劑包括m-CPBA，且反應溫度通常為0℃至室溫且較佳為室溫。較佳地，溶劑包括二氯甲烷及氯仿。在後一種情況下，適合之烷基化試劑包括碘代甲烷，且適合之鹼包括氫化鈉、碳酸氫鈉及碳酸鉀。 The compound of the formula (A6) can be used by using an agent such as m-CPBA, hydrogen peroxide and a carbodiimide reagent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. Preparation of the cyclization reaction of (A5). Alternatively, the compound of formula (A6) can be obtained by reacting (A5) with an alkylating agent followed by a cyclization reaction under basic conditions. In the former case, suitable reagents include m-CPBA, and the reaction temperature is usually from 0 ° C to room temperature and preferably room temperature. Preferably, the solvent comprises dichloromethane and chloroform. In the latter case, suitable alkylating agents include methyl iodide, and suitable bases include sodium hydride, sodium bicarbonate, and potassium carbonate.

步驟6： Step 6:

式(Ia)化合物可藉由以下反應順序製備：1)Y=H；式(A6)中之P2之去除保護基、硝化、保護、還原，繼之以與胺之醯胺偶合反應，獲得式(Ia)化合物，2)Y=Br或I；式(A6)與醯胺之布赫瓦爾德-哈特維希反應(Buchwald-Hartwig reaction)，繼之以P2之去除保護基，獲得式(Ia)化合物，3)Y=三氟乙醯基胺基；三氟乙醯基胺基之去除保護基，醯胺偶合反應，繼之以P2之去除保護基，獲得式(Ia)化合物。1)至3)之 反應條件之實例為下文所述：1)Y=H：式(A6)化合物可在Greene's Protective Groups in Organic Synthesis中所述之條件下去除保護基。當P2為苯甲醯基時，去除保護基可在室溫至80℃下使用諸如甲醇及乙醇之溶劑藉由諸如水合肼或碳酸鉀之鹼進行。 The compound of the formula (Ia) can be produced by the following reaction sequence: 1) Y = H; removal of the protecting group of P 2 in the formula (A6), nitration, protection, reduction, followed by coupling reaction with an amine amide a compound of the formula (Ia), 2) Y = Br or I; a Buchwald-Hartwig reaction of the formula (A6) with decylamine, followed by removal of the protecting group by P 2 a compound of the formula (Ia), 3) Y = trifluoroacetamidoamine; a protecting group for the trifluoroethenylamine group, a guanamine coupling reaction, followed by removal of the protecting group by P 2 to obtain the formula (Ia) Compound. Examples of the reaction conditions of 1) to 3) are as follows: 1) Y = H: The compound of the formula (A6) can be removed under the conditions described in Greene's Protective Groups in Organic Synthesis. When P 2 is a benzamidine group, the removal of the protecting group can be carried out by using a solvent such as methanol or ethanol at room temperature to 80 ° C by a base such as hydrazine hydrate or potassium carbonate.

去除保護基化合物之硝化可藉由熟習此項技術者已知之方法進行。舉例而言，硝化化合物可藉由在溶劑，諸如硫酸或硫酸及三氟乙酸之混合溶劑中使用硝酸或硝酸酯獲得。反應溫度通常為-20℃至0℃。反應時間通常為1分鐘至1小時。 Removal of the nitration of the protecting group compound can be carried out by methods known to those skilled in the art. For example, the nitrating compound can be obtained by using nitric acid or a nitrate ester in a solvent such as sulfuric acid or a mixed solvent of sulfuric acid and trifluoroacetic acid. The reaction temperature is usually -20 ° C to 0 ° C. The reaction time is usually from 1 minute to 1 hour.

去除保護基化合物中之脒基可在Greene's Protective Groups in Organic Synthesis中所述之條件下經Boc保護。舉例而言，Boc保護可在室溫至50℃下在諸如二氯甲烷及四氫呋喃之溶劑中使用Boc2O及催化量之N,N-二甲基-4-胺基吡啶進行。 Removal of the thiol group in the protecting group compound can be protected by Boc under the conditions described in Greene's Protective Groups in Organic Synthesis. For example, Boc protection can be carried out using Boc 2 O and a catalytic amount of N,N-dimethyl-4-aminopyridine in a solvent such as dichloromethane and tetrahydrofuran at room temperature to 50 °C.

硝化化合物之還原可藉由熟習此項技術者已知之方法進行以獲得對應苯胺；可使用以下條件：1)在氫氯酸或氯化銨存在下使用鐵粉之方法；2)在氫氣氛圍下使用鈀/碳之方法。溶劑之實例包括諸如水、甲醇、乙醇、乙酸乙酯、四氫呋喃之溶劑，及彼等溶劑之混合物。 The reduction of the nitrated compound can be carried out by methods known to those skilled in the art to obtain the corresponding aniline; the following conditions can be used: 1) a method of using iron powder in the presence of hydrochloric acid or ammonium chloride; 2) under a hydrogen atmosphere Use the palladium/carbon method. Examples of the solvent include a solvent such as water, methanol, ethanol, ethyl acetate, tetrahydrofuran, and a mixture of these solvents.

苯胺與胺之醯胺偶合反應可藉由熟習此項技術者已知之方法進行，且適合之偶合條件可見於Chem.Rev.2011,111,6557-6602中，其包括：a)使用縮合試劑之反應；b)使用酸氯化物或氟化物之反應。 The indole coupling reaction of aniline with an amine can be carried out by methods known to those skilled in the art, and suitable coupling conditions can be found in Chem. Rev. 2011, 111, 6557-6602, which comprises: a) using a condensation reagent Reaction; b) reaction using acid chloride or fluoride.

反應a)可藉由使用諸如二環己基碳化二亞胺(DCC)、二異丙基碳化二亞胺(DIC)、1-乙基-3-(3-二甲胺基丙基)碳化二亞胺鹽酸鹽(EDC鹽酸鹽)、O-(7-氮雜-1H-苯并***-1-基)-N,N,N',N'-四甲基釒尿六氟磷酸鹽(HATU)及1H-苯并***-1-基氧基-三(N-吡咯啶基)鏻六氟磷酸鹽 (PyBOP)之縮合試劑進行。當使用釒尿或鏻鹽，諸如HATU及PyBOP時，反應可在諸如三乙胺及二異丙基乙胺之鹼存在下進行。反應可藉由使用諸如1-羥基-苯并***(HOBt)及1-羥基-7-氮雜-苯并***(HOAt)之催化劑加速。用於反應中之溶劑在其不干擾反應之程度上不受特別限制。溶劑之實例包括二氯甲烷、N,N-二甲基甲醯胺、N-甲基吡咯啶酮及四氫呋喃。反應溫度通常為0℃至50℃且較佳為室溫。 Reaction a) can be carbonized by using, for example, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl) Imine hydrochloride (EDC hydrochloride), O-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylguanidine hexafluorophosphate Salt (HATU) and 1H-benzotriazol-1-yloxy-tris(N-pyrrolidinyl)phosphonium hexafluorophosphate The condensation reagent of (PyBOP) is carried out. When a guanidine or guanidine salt such as HATU and PyBOP is used, the reaction can be carried out in the presence of a base such as triethylamine and diisopropylethylamine. The reaction can be accelerated by using a catalyst such as 1-hydroxy-benzotriazole (HOBt) and 1-hydroxy-7-aza-benzotriazole (HOAt). The solvent used in the reaction is not particularly limited to the extent that it does not interfere with the reaction. Examples of the solvent include dichloromethane, N,N-dimethylformamide, N-methylpyrrolidone, and tetrahydrofuran. The reaction temperature is usually from 0 ° C to 50 ° C and preferably room temperature.

反應b)可藉由在諸如三乙胺、二異丙基乙胺、吡啶及N,N-二甲基-4-胺基吡啶之鹼存在下在諸如二氯甲烷、四氫呋喃及乙酸乙酯之溶劑中使用市售酸氯化物或藉由熟習此項技術者已知之方法合成之彼等者進行。反應溫度通常為0℃至60℃且較佳為0℃至室溫。反應時間不受特別限制且通常為5分鐘至24小時，較佳為20分鐘至6小時。 Reaction b) can be carried out in the presence of a base such as triethylamine, diisopropylethylamine, pyridine and N,N-dimethyl-4-aminopyridine in dichloromethane, tetrahydrofuran and ethyl acetate. The use of commercially available acid chlorides in solvents is carried out by those skilled in the art by methods known to those skilled in the art. The reaction temperature is usually from 0 ° C to 60 ° C and preferably from 0 ° C to room temperature. The reaction time is not particularly limited and is usually from 5 minutes to 24 hours, preferably from 20 minutes to 6 hours.

2)Y=Br或I：式(A6)化合物與醯胺衍生物之布赫瓦爾德-哈特維希反應可藉由Metal-Catalyzed Cross-Coupling Reactions，第2版中所述之方法進行。舉例而言，此反應可藉由在諸如第三丁醇鈉、碳酸銫及磷酸鉀之鹼存在下使用諸如參(二苯亞甲基丙酮)二鈀及乙酸鈀之過渡金屬催化劑及諸如2,2'-雙(二苯膦基)-1,1'-聯萘(BINAP)、4,5-雙(二苯膦基)-9,9-二甲基二苯并哌喃(氧雜蒽膦)及2-二環己基膦基-2',4',6'-三異丙基聯苯(X-Phos)之配體進行。反應溫度通常為40℃至150℃且較佳為60℃至100℃。此反應可藉由微波照射加速。溶劑之實例包括甲苯、苯、二甲苯、四氫呋喃、1,4-二烷及1,2-二甲氧乙烷。 2) Y = Br or I: The Buchwald-Hartwig reaction of the compound of the formula (A6) with the guanamine derivative can be carried out by the method described in Metal-Catalyzed Cross-Coupling Reactions, 2nd edition. For example, the reaction can be carried out by using a transition metal catalyst such as bis(diphenylmethyleneacetone)dipalladium and palladium acetate and such as 2 in the presence of a base such as sodium butoxide, cesium carbonate and potassium phosphate. 2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (oxanthene) Ligand) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos) ligands were carried out. The reaction temperature is usually from 40 ° C to 150 ° C and preferably from 60 ° C to 100 ° C. This reaction can be accelerated by microwave irradiation. Examples of the solvent include toluene, benzene, xylene, tetrahydrofuran, 1,4-two Alkane and 1,2-dimethoxyethane.

在布赫瓦爾德-哈特維希反應之後，所得化合物中之P2之去除保護基可在上文所述之條件下進行。 After the Buchwald-Hartwig reaction, the removal of the protecting group of P 2 in the obtained compound can be carried out under the conditions described above.

3)Y=三氟乙醯基胺基：式(A6)化合物中之三氟乙醯基胺基之去除保護基可藉由熟習此項技術者已知之方法進行。適合之條件可見於Greene's Protective Groups in Organic Synthesis中。舉例而言，常用方法可為(但不限於)在室溫下使用甲醇中之碳酸鉀。後續醯胺偶合反應及P2之去除保護基可在與上文所述相同之條件下進行。 3) Y = trifluoroacetamidoamine: The removal of the trifluoroethenylamine group in the compound of formula (A6) can be carried out by methods known to those skilled in the art. Suitable conditions can be found in Greene's Protective Groups in Organic Synthesis. For example, a common method can be, but is not limited to, using potassium carbonate in methanol at room temperature. The subsequent indoleamine coupling reaction and the removal of the protecting group of P 2 can be carried out under the same conditions as described above.

一般程序B： General procedure B:

其中符號與一般程序A中所定義相同。 The symbols are the same as defined in General Procedure A.

一般程序B為一種經由多個步驟自式(A5)化合物製備式(Ib)化合物之方法。使用式(B1)化合物，式(Ib)化合物可根據一般程序A中所述之方法製備。 General Procedure B is a process for the preparation of a compound of formula (Ib) from a compound of formula (A5) via multiple steps. Using a compound of formula (B1), the compound of formula (Ib) can be prepared according to the procedures described in General Procedure A.

步驟1： step 1:

式(B1)化合物可藉由將羥基轉化為諸如Cl、Br及三氟甲磺酸酯基之離去基之式(A5)化合物之環化反應製備。反應條件為熟習此項技術者已知。舉例而言，可使用諸如1-氯-N,N,2-三甲基丙烯基胺之試劑達成氯化繼之以環化。或者，可在諸如N,N-二甲基-4-胺基吡啶及吡啶之鹼存在下使用三氟甲磺酸酐。溶劑之實例包括二氯甲烷及四氫呋喃。反應溫度通常為0℃至室溫且較佳為0℃。反應時間不受特別限制且通常為0.5至3小時。 The compound of the formula (B1) can be produced by a cyclization reaction of a compound of the formula (A5) which converts a hydroxyl group into a leaving group such as Cl, Br and a triflate group. The reaction conditions are known to those skilled in the art. For example, chlorination can be achieved using a reagent such as 1-chloro-N,N,2-trimethylpropenylamine followed by cyclization. Alternatively, trifluoromethanesulfonic anhydride can be used in the presence of a base such as N,N-dimethyl-4-aminopyridine and pyridine. Examples of the solvent include dichloromethane and tetrahydrofuran. The reaction temperature is usually from 0 ° C to room temperature and preferably from 0 ° C. The reaction time is not particularly limited and is usually from 0.5 to 3 hours.

一般程序C： General procedure C:

[化學式47] [Chemical Formula 47]

其中Hal為鹵素，R3a'及R3b'各自獨立地為氫或烷基，且其他符號與一般程序A中所定義相同。 Wherein Hal is halogen, R 3a' and R 3b' are each independently hydrogen or alkyl, and the other symbols are the same as defined in general procedure A.

一般程序C為一種經由多個步驟自式(A3)化合物製備式(Ic)化合物之方法。使用式(C6)化合物，式(Ic)化合物可根據一般程序A中所述之方法製備。 General Procedure C is a process for the preparation of a compound of formula (Ic) from a compound of formula (A3) via multiple steps. Using a compound of formula (C6), the compound of formula (Ic) can be prepared according to the procedures described in General Procedure A.

步驟1： step 1:

式(C1)化合物可藉由式(A3)化合物之脲形成製備。此類型之反應為熟習此項技術者已知且通常藉由用諸如三光氣、氯甲酸4-硝基苯酯及羰基二咪唑之試劑處理式(A3)化合物，接著添加諸如雙(2,4-二甲氧基苯甲基)胺之胺進行。此等試劑之較佳組合可為氯甲酸4-硝基苯酯及雙(2,4-二甲氧基苯甲基)胺。在該情況下，反應可在諸如碳酸氫鈉之鹼存在下在溶劑，諸如水、四氫呋喃、乙酸乙酯及此等溶劑之混合 物中進行。反應溫度通常為0℃至室溫。反應時間不受特別限制且通常為1至12小時。 The compound of the formula (C1) can be produced by the formation of a urea of the compound of the formula (A3). This type of reaction is known to those skilled in the art and is usually treated with a reagent such as triphosgene, 4-nitrophenyl chloroformate and carbonyldiimidazole, followed by addition such as bis (2, 4). The amine of -dimethoxybenzyl)amine is carried out. A preferred combination of such agents can be 4-nitrophenyl chloroformate and bis(2,4-dimethoxybenzyl)amine. In this case, the reaction can be carried out in a solvent such as water, tetrahydrofuran, ethyl acetate and the like in the presence of a base such as sodium hydrogencarbonate. In the matter. The reaction temperature is usually from 0 ° C to room temperature. The reaction time is not particularly limited and is usually from 1 to 12 hours.

步驟2： Step 2:

式(C2)化合物可藉由式(C1)化合物之還原製備。此反應為熟習此項技術者已知且通常使用二異丁基氫化鋁(DIBAL-H)預成型。溶劑之實例包括二氯甲烷、四氫呋喃及甲苯。反應溫度通常低於-60℃且較佳低於-70℃。反應時間不受特別限制且通常為1至12小時。 Compounds of formula (C2) can be prepared by reduction of a compound of formula (C1). This reaction is known to those skilled in the art and is typically preformed using diisobutylaluminum hydride (DIBAL-H). Examples of the solvent include dichloromethane, tetrahydrofuran, and toluene. The reaction temperature is usually lower than -60 ° C and preferably lower than -70 ° C. The reaction time is not particularly limited and is usually from 1 to 12 hours.

步驟3 Step 3

式(C3)化合物可藉由式(C2)化合物與對應鏻偶極體之維蒂希反應(Wittig reaction)製備。或者，可考慮彼得森稀化作用(Peterson olefination)、霍納-沃茲沃茨-埃蒙斯反應(Horner-Wadsworth-Emmons reaction)、朱麗亞偶合(Julia coupling)及克諾文諾蓋爾縮合(Knoevenagel condensation)。此等反應為熟習此項技術者已知。舉例而言，維蒂希反應可一般藉由用三苯膦繼之以諸如正丁基鋰之鹼處理對應烷基鹵化物，其可隨後添加至諸如四氫呋喃之溶劑中之式(C3)化合物而進行。反應時間不受特別限制且通常為1至12小時。 The compound of the formula (C3) can be produced by the Wittig reaction of the compound of the formula (C2) with the corresponding oxime dipole. Alternatively, consider Peterson olefination, Horner-Wadsworth-Emmons reaction, Julia coupling, and Knovenogell condensation. Knoevenagel condensation). Such reactions are known to those skilled in the art. For example, the Wittig reaction can generally be carried out by treating the corresponding alkyl halide with triphenylphosphine followed by a base such as n-butyllithium, which can then be added to a compound of formula (C3) in a solvent such as tetrahydrofuran. get on. The reaction time is not particularly limited and is usually from 1 to 12 hours.

步驟4： Step 4:

式(C4)化合物可藉由使用碘之式(C3)化合物之環化製備。溶劑之實例包括乙腈、四氫呋喃及二氯甲烷。反應溫度通常為0℃至50℃且較佳為室溫。反應時間不受特別限制且通常為1至12小時。 The compound of the formula (C4) can be produced by cyclization of a compound of the formula (C3) using iodine. Examples of the solvent include acetonitrile, tetrahydrofuran, and dichloromethane. The reaction temperature is usually from 0 ° C to 50 ° C and preferably room temperature. The reaction time is not particularly limited and is usually from 1 to 12 hours.

步驟5： Step 5:

式(C5)化合物可藉由1)式(C4)化合物之鹵化；2)式(C4)化合物之羥基化繼之以對應醇之去氧鹵化製備。 The compound of formula (C5) can be prepared by halogenation of 1) a compound of formula (C4); 2) hydroxylation of a compound of formula (C4) followed by deoxyhalogenation of the corresponding alcohol.

對於1)，式(C4)化合物之鹵化(例如氟化)可用諸如氟化四丁銨(TBAF)之試劑進行。溶劑之實例包括乙腈及四氫呋喃。反應溫度通常為0℃至50℃且較佳為室溫。反應時間不受特別限制且通常為1至12 小時。 For 1), halogenation (e.g., fluorination) of a compound of formula (C4) can be carried out using a reagent such as tetrabutylammonium fluoride (TBAF). Examples of the solvent include acetonitrile and tetrahydrofuran. The reaction temperature is usually from 0 ° C to 50 ° C and preferably room temperature. The reaction time is not particularly limited and is usually from 1 to 12 hour.

對於2)，式(C4)化合物之羥基化可用諸如超氧化鉀(KO2)、三氟乙酸銀及三氟硼酸銀之試劑進行。溶劑之較佳實例包括就KO2而言之二甲亞碸(DMSO)、就三氟乙酸銀而言之硝基甲烷-水，及就三氟硼酸銀而言之DMSO-水。反應溫度不受特別限制且較佳為就KO2而言之室溫、就三氟乙酸銀而言之60℃至80℃，及就三氟硼酸銀而言之60℃至80℃。後續去氧鹵化(例如去氧氟化)可用諸如N,N-三氟化二乙基胺基硫(DAST)及三氟化雙(2-甲氧基乙基)胺基硫(脫氧加氟物(Deoxofluor)；商標)之試劑進行。溶劑之實例包括二氯甲烷、乙腈及四氫呋喃。反應溫度通常為-78℃至室溫且較佳為-78℃至0℃。替代條件可發現於合成2002,2561-2578中。 For 2), the hydroxylation of the compound of formula (C4) can be carried out using reagents such as potassium superoxide (KO 2 ), silver trifluoroacetate and silver trifluoroborate. Preferred examples of the solvent include dimethyl hydrazine (DMSO) for KO 2 , nitromethane-water for silver trifluoroacetate, and DMSO-water for silver trifluoroborate. The reaction temperature is not particularly limited and is preferably room temperature in terms of KO 2 , 60 ° C to 80 ° C in terms of silver trifluoroacetate, and 60 ° C to 80 ° C in terms of silver trifluoroborate. Subsequent deoxyhalogenation (eg deoxyfluorination) may be carried out with, for example, N,N-diethylammonium trifluoride (DAST) and bis(2-methoxyethyl)aminosulfur trifluoride (deoxyfluoride) Reagent (Deoxofluor); trademark) reagent. Examples of the solvent include dichloromethane, acetonitrile, and tetrahydrofuran. The reaction temperature is usually -78 ° C to room temperature and preferably -78 ° C to 0 ° C. Alternative conditions can be found in Synthesis 2002, 2561-2578.

一般程序D： General procedure D:

其中符號與一般程序A中所定義相同。 The symbols are the same as defined in General Procedure A.

一般程序D為一種經由多個步驟自式(D1)化合物製備式(I)化合物之方法。使用式(A5)化合物，式(I)化合物可根據一般程序A及B中所述之方法製備。式(D1)之起始物質可以與Chem.Rev.2010,110,3600-3740中所述之條件類似之方式製備。 General Procedure D is a process for the preparation of a compound of formula (I) from a compound of formula (D1) via multiple steps. Using a compound of formula (A5), the compound of formula (I) can be prepared according to the procedures described in General Procedures A and B. The starting material of formula (D1) can be prepared in a manner similar to that described in Chem. Rev. 2010, 110, 3600-3740.

步驟1： step 1:

式(D2)化合物可藉由添加式(D1)化合物至式(R3aCOR3b)之酮製備。此反應可在與Chem.Rev.2010,110,3600-3740中所述之彼等條件類似之條件下進行。舉例而言，來源於式(D1)之酮亞胺可使用二異丙胺基鋰，接著添加酮(R3aCOR3b)製備，獲得(D2)。溶劑之實例包括四氫呋喃及甲苯。反應溫度通常低於-60℃且較佳低於-70℃。反應時間不受特別限制且通常為1至12小時。 The compound of the formula (D2) can be produced by adding a compound of the formula (D1) to a ketone of the formula (R 3a COR 3b ). This reaction can be carried out under conditions similar to those described in Chem. Rev. 2010, 110, 3600-3740. For example, a ketimine derived from the formula (D1) can be produced using lithium diisopropylamide followed by the addition of a ketone (R 3a COR 3b ) to obtain (D2). Examples of the solvent include tetrahydrofuran and toluene. The reaction temperature is usually lower than -60 ° C and preferably lower than -70 ° C. The reaction time is not particularly limited and is usually from 1 to 12 hours.

步驟2： Step 2:

式(D3)化合物可藉由(D2)與諸如溴化甲基鎂及溴化乙基鎂之格林納試劑(Grignard reagent)及諸如甲基鋰、丁基鋰及苯基鋰之烷基鋰試劑之反應製備。溶劑在其不干擾反應之程度上不受特別限制。溶劑之較佳實例包括四氫呋喃、1,4-二烷、1,2-二甲氧乙烷、***、甲苯及苯。反應溫度不受特別限制且通常為5分鐘至24小時，較佳為5分鐘至6小時。反應溫度通常為-78℃至室溫且較佳為-78℃至-40℃。 The compound of the formula (D3) can be obtained by (D2) with a Grignard reagent such as methylmagnesium bromide and ethylmagnesium bromide, and an alkyllithium reagent such as methyllithium, butyllithium and phenyllithium. The reaction was prepared. The solvent is not particularly limited to the extent that it does not interfere with the reaction. Preferred examples of the solvent include tetrahydrofuran, 1,4-two Alkane, 1,2-dimethoxyethane, diethyl ether, toluene and benzene. The reaction temperature is not particularly limited and is usually from 5 minutes to 24 hours, preferably from 5 minutes to 6 hours. The reaction temperature is usually -78 ° C to room temperature and preferably -78 ° C to -40 ° C.

步驟3： Step 3:

式(D4)化合物可根據一般程序A之步驟2中所描述之方法製備。 The compound of formula (D4) can be prepared according to the procedure described in Step 2 of General Procedure A.

步驟4： Step 4:

式(A5)化合物可根據一般程序A之步驟3中所描述之方法製備。一般程序E：[化學式49] The compound of formula (A5) can be prepared according to the procedure described in Step 3 of General Procedure A. General procedure E: [Chemical Formula 49]

其中P為羥基之保護基，諸如苯甲基及第三丁基二甲基矽烷基，R為烷基或鹵烷基，且其他符號與一般程序A中所定義相同。 Wherein P is a protecting group for a hydroxyl group, such as benzyl and tert-butyldimethylalkyl, R is alkyl or haloalkyl, and the other symbols are the same as defined in general procedure A.

一般程序E為一種經由多個步驟自式(E1)化合物製備式(I)化合物之方法。使用式(E8)化合物，式(I)化合物可根據一般程序A及B中所述之方法製備。 General Procedure E is a process for the preparation of a compound of formula (I) from a compound of formula (E1) via multiple steps. Using a compound of formula (E8), the compound of formula (I) can be prepared according to the procedures described in General Procedures A and B.

步驟1： step 1:

式(E2)化合物可藉由在催化量之諸如TBAF、氟化銫及氟化鉀之鹼之存在下的諸如Me3SiCF3、Me3SiCHF2及Me3SiCH2F之加成反應製備。溶劑之實例包括四氫呋喃、N,N-二甲基甲醯胺(DMF)、乙腈及甲苯。反應溫度通常為-20℃至室溫且較佳為室溫。或者，此反應可藉由使用烷基或鹵烷基鈰試劑(藉由氯化鈰(III)製備)及烷基鋰或格林納試劑進行，獲得式(E2)化合物。使用無氯化鈰(III)之烷基或鹵烷基鋰或格林納試劑可根據熟習此項技術者已知之方法提供(E2)。 The compound of the formula (E2) can be produced by an addition reaction such as Me 3 SiCF 3 , Me 3 SiCHF 2 and Me 3 SiCH 2 F in the presence of a catalytic amount of a base such as TBAF, cesium fluoride and potassium fluoride. Examples of the solvent include tetrahydrofuran, N,N-dimethylformamide (DMF), acetonitrile, and toluene. The reaction temperature is usually -20 ° C to room temperature and preferably room temperature. Alternatively, the reaction can be carried out by using an alkyl or haloalkyl hydrazine reagent (prepared by ruthenium (III) chloride) and an alkyl lithium or a Grignard reagent to obtain a compound of the formula (E2). The use of an alkyl or haloalkyllithium chloride or Grignard reagent without ruthenium (III) chloride can be provided according to methods known to those skilled in the art (E2).

步驟2： Step 2:

式(E3)化合物可藉由式(E2)化合物之環氧化製備。環氧化為熟習此項技術者已知的且藉由使用諸如二氯甲烷及氯仿之溶劑中之諸如m-CPBA及第三丁基氫過氧化物之氧化劑進行。反應時間不受特別限制且通常為0.5至3小時。反應溫度通常為-50℃至室溫。諸如夏普利斯不對稱環氧化(Sharpless asymmetric epoxidation)之不對稱環氧化亦可使用熟習此項技術者已知之方法應用於此步驟，其可有助於在不進行對掌性分離的情況下合成對掌性化合物。適合之條件可見於Comprehensive Organic Synthesis 1991,7,389中。 Compounds of formula (E3) can be prepared by epoxidation of a compound of formula (E2). Epoxidation is known to those skilled in the art and is carried out by using an oxidizing agent such as m-CPBA and a third butyl hydroperoxide in a solvent such as dichloromethane and chloroform. The reaction time is not particularly limited and is usually from 0.5 to 3 hours. The reaction temperature is usually -50 ° C to room temperature. Asymmetric epoxidation, such as Sharpless asymmetric epoxidation, can also be applied to this step using methods known to those skilled in the art, which can aid in the synthesis without the separation of palms. For palm compounds. Suitable conditions can be found in Comprehensive Organic Synthesis 1991, 7, 389.

步驟3： Step 3:

式(E4)化合物可藉由在諸如Ti(OEt)4之路易斯酸(Lewis acid)存在下使用疊氮化鈉之式(E3)化合物之開環反應製備。溶劑之實例包括諸如四氫呋喃、甲苯及***之溶劑。反應時間不受特別限制且通常為1至24小時。反應溫度通常為室溫。 The compound of the formula (E4) can be produced by a ring-opening reaction of a compound of the formula (E3) using sodium azide in the presence of a Lewis acid such as Ti(OEt) 4 . Examples of the solvent include solvents such as tetrahydrofuran, toluene and diethyl ether. The reaction time is not particularly limited and is usually from 1 to 24 hours. The reaction temperature is usually room temperature.

步驟4： Step 4:

式(E4)化合物之保護可藉由溴甲苯或第三丁基二甲基矽烷基氯進行，獲得式(E5)化合物。當藉由苯甲基保護時，保護可在氧化(二丁基)錫存在下使用溴甲苯進行。溶劑之實例包括甲苯、甲醇、DMF及此等混合溶劑。反應溫度通常為60℃至100℃。當藉由第三丁基二甲基矽烷基保護時，適合之條件可見於Greene's Protective Groups in Organic Synthesis中。舉例而言，保護可在作為鹼之咪唑存在下使用第三丁基二甲基矽烷基氯進行。溶劑之實例包括四氫呋喃、二氯甲烷及DMF。反應溫度通常為0℃至室溫。 The protection of the compound of the formula (E4) can be carried out by using bromotoluene or tert-butyldimethylsilyl chloride to obtain a compound of the formula (E5). When protected by benzylation, the protection can be carried out using bromotoluene in the presence of oxidized (dibutyl)tin. Examples of the solvent include toluene, methanol, DMF, and a mixed solvent thereof. The reaction temperature is usually from 60 ° C to 100 ° C. Suitable conditions are found in Greene's Protective Groups in Organic Synthesis when protected by a third butyl dimethyl decyl group. For example, the protection can be carried out using a third butyl dimethyl decyl chloride in the presence of an imidazole as a base. Examples of the solvent include tetrahydrofuran, dichloromethane, and DMF. The reaction temperature is usually from 0 ° C to room temperature.

步驟5： Step 5:

式(E6)化合物可藉由式(E5)化合物之烷基化製備。此反應為熟習此項技術者已知且通常在諸如氫化鈉、碳酸鉀及碳酸鈉之鹼存在下使用諸如烷基碘、烷基溴及烷基三氟甲磺酸鹽之烷基化試劑進行。溶劑 之實例包括四氫呋喃、DMF、甲苯、丙酮及乙腈。反應溫度通常為0℃至室溫。 Compounds of formula (E6) can be prepared by alkylation of a compound of formula (E5). This reaction is known to those skilled in the art and is typically carried out using an alkylating agent such as alkyl iodide, alkyl bromide and alkyl triflate in the presence of a base such as sodium hydride, potassium carbonate and sodium carbonate. . Solvent Examples include tetrahydrofuran, DMF, toluene, acetone, and acetonitrile. The reaction temperature is usually from 0 ° C to room temperature.

步驟6： Step 6:

式(E7)化合物可在與Greene's Protective Groups in Organic Synthesis中所述之彼等條件類似之條件下去除保護基。舉例而言，當P為苯甲基時，去除保護基可藉由在催化量之鈀/碳或氫氧化鈀存在下之氫化進行。當P為第三丁基二甲基矽烷基時，去除保護基可在0℃至室溫下藉由諸如四氫呋喃之溶劑中之TBAF進行。 The compound of formula (E7) can be removed under conditions similar to those described in Greene's Protective Groups in Organic Synthesis. For example, when P is a benzyl group, removal of the protecting group can be carried out by hydrogenation in the presence of a catalytic amount of palladium on carbon or palladium hydroxide. When P is a third butyl dimethyl decyl group, the removal of the protecting group can be carried out at 0 ° C to room temperature by TBAF in a solvent such as tetrahydrofuran.

一般程序F： General procedure F:

其中P1為烷基；P2為羥基之保護基，諸如第三丁基二甲基矽烷基；P3為甲磺醯基或甲苯磺醯基，且其他符號與一般來說程序A中所定義相同。 Wherein P 1 is an alkyl group; P 2 is a protecting group for a hydroxyl group such as a tert-butyldimethylmethylalkyl group; P 3 is a methylsulfonyl group or a toluenesulfonyl group, and other symbols are generally used in the procedure A. The definition is the same.

一般程序F為一種經由多個步驟自式(E1)化合物製備式(If)化合物之方法。使用式(F9)化合物，式(I)化合物可根據一般程序A及B中所述之方法製備。 General Procedure F is a process for the preparation of a compound of formula (If) from a compound of formula (E1) via multiple steps. Using a compound of formula (F9), the compound of formula (I) can be prepared according to the procedures described in General Procedures A and B.

步驟1： step 1:

式(F1)化合物可藉由式(E1)化合物與α-鹵酯之瑞福馬斯基反應(Reformatsky reaction)製備。此反應為熟習此項技術者已知且通常在Tetrahedron 2004,42,9325-9374中所述之條件下進行。舉例而言，諸如四氫呋喃、乙腈及甲苯之溶劑中之式(F1)化合物及α-鹵酯之混合物在鋅粉存在下在室溫至100℃下反應。反應時間不受特別限制且通常為1小時至12小時。 The compound of the formula (F1) can be produced by a Reformatsky reaction of a compound of the formula (E1) with an α-haloester. This reaction is known to those skilled in the art and is generally carried out under the conditions described in Tetrahedron 2004, 42, 9325-9374. For example, a mixture of a compound of the formula (F1) and an α-haloester in a solvent such as tetrahydrofuran, acetonitrile and toluene is reacted in the presence of zinc powder at room temperature to 100 °C. The reaction time is not particularly limited and is usually from 1 hour to 12 hours.

步驟2： Step 2:

式(F2)化合物可藉由一般程序C之步驟2中所描述之方法製備。 Compounds of formula (F2) can be prepared by the methods described in Step 2 of General Procedure C.

步驟3： Step 3:

式(F3)化合物可藉由式(F2)之醇之保護而製備。保護基可取決於用於下一步驟中之反應條件選擇。適合之保護基可見於Greene's Protective Groups in Organic Synthesis中。舉例而言，當選擇第三丁基二甲基矽烷基時，保護可在諸如咪唑及氫化鈉之鹼存在下在諸如DMF、四氫呋喃及乙腈之溶劑中在0℃至室溫下使用第三丁基二甲基矽烷基氯進行。反應時間不受特別限制且通常為0.5至6小時。若產率較低，則使用三氟甲磺酸第三丁基二甲基矽烷基酯代替對應氯化物可為恰當選擇。 The compound of the formula (F3) can be produced by the protection of the alcohol of the formula (F2). The protecting group can be selected depending on the reaction conditions used in the next step. Suitable protecting groups can be found in Greene's Protective Groups in Organic Synthesis. For example, when a third butyl dimethyl decyl group is selected, the protection can be carried out in a solvent such as DMF, tetrahydrofuran and acetonitrile in the presence of a base such as imidazole and sodium hydride at 0 ° C to room temperature. The dimethyl decyl chloride is carried out. The reaction time is not particularly limited and is usually from 0.5 to 6 hours. If the yield is low, the use of tributyl dimethyl sulfamate trifluoromethanesulfonate in place of the corresponding chloride may be a suitable choice.

步驟4： Step 4:

式(F4)化合物可根據一般程序E之步驟2中所述之條件製備。 The compound of formula (F4) can be prepared according to the conditions described in Step 2 of General Procedure E.

步驟5： Step 5:

式(F5)化合物可藉由式(F4)化合物之去除保護基製備。取決於式(F4)中之保護基，去除保護基條件可根據Greene's Protective Groups in Organic Synthesis選擇。當P2為第三丁基二甲基矽烷基時，去除保護基可在諸如四氫呋喃、DMF及乙腈之溶劑中在0℃至室溫下使用TBAF進行。反應時間不受特別限制且通常為0.5至6小時。 The compound of the formula (F5) can be produced by removing the protecting group of the compound of the formula (F4). Depending on the protecting group in formula (F4), the removal of protecting groups can be selected according to Greene's Protective Groups in Organic Synthesis. When P2 is a third butyl dimethyl decyl group, the removal of the protecting group can be carried out using TBAF at 0 ° C to room temperature in a solvent such as tetrahydrofuran, DMF and acetonitrile. The reaction time is not particularly limited and is usually from 0.5 to 6 hours.

步驟6： Step 6:

式(F6)化合物可根據一般程序E之步驟3中所述之條件製備。 The compound of formula (F6) can be prepared according to the conditions described in Step 3 of General Procedure E.

步驟7： Step 7:

式(F6)化合物之末端醇可在此步驟中轉化成對應離去基，諸如甲磺酸酯基或甲苯磺酸酯基。此反應為熟習此項技術者已知且通常根據Greene's Protective Groups in Organic Synthesis中所描述之方法進行。 舉例而言，甲苯磺醯基之保護可在諸如N,N-二甲胺基-4-吡啶、吡啶及三乙胺之鹼存在下在諸如二氯甲烷、四氫呋喃及乙腈之溶劑中在0℃至室溫下使用甲苯磺醯氯進行。反應時間不受特別限制且通常為0.5至6小時。 The terminal alcohol of the compound of formula (F6) can be converted to the corresponding leaving group, such as a mesylate or tosylate group, in this step. This reaction is known to those skilled in the art and is generally carried out according to the methods described in Greene's Protective Groups in Organic Synthesis. For example, the toluenesulfonyl group can be protected at 0 ° C in the presence of a base such as N,N-dimethylamino-4-pyridine, pyridine and triethylamine in a solvent such as dichloromethane, tetrahydrofuran and acetonitrile. It was carried out using toluene sulfonium chloride at room temperature. The reaction time is not particularly limited and is usually from 0.5 to 6 hours.

步驟8 Step 8

式(F8)化合物可藉由式(F7)化合物之環化製備。此反應可藉由在諸如甲醇、乙醇及丙酮之溶劑中在室溫下使用諸如碳酸鉀及碳酸鈉之鹼達成。反應時間不受特別限制且通常為1至6小時。 Compounds of formula (F8) can be prepared by cyclization of a compound of formula (F7). This reaction can be achieved by using a base such as potassium carbonate and sodium carbonate at room temperature in a solvent such as methanol, ethanol and acetone. The reaction time is not particularly limited and is usually from 1 to 6 hours.

步驟9： Step 9:

式(F9)化合物可根據一般程序E之步驟4中所述之條件製備。 The compound of formula (F9) can be prepared according to the conditions described in Step 4 of General Procedure E.

本發明化合物具有BACE1抑制活性且在治療及/或預防藉由澱粉狀蛋白β蛋白之產生、分泌或沈積誘發之疾病、其症狀改良及預防其進展中有效，該疾病為諸如阿茲海默氏病、阿茲海默癡呆症、阿茲海默型老年癡呆症、輕度認知障礙(MCI)、前驅性阿茲海默氏病(例如由 於阿茲海默氏病之MCI)、唐氏症候群(Down's syndrome)、記憶障礙、朊病毒疾病(庫賈氏病(Creutzfeldt-Jakob disease))、荷蘭型出現澱粉樣變性之遺傳性腦出血、大腦澱粉狀蛋白血管病、其他類型之退化性癡呆、諸如共存阿茲海默氏病與血管型癡呆、癡呆與帕金森氏病、癡呆與進行性核上麻痹、癡呆與皮層基底節變性、阿茲海默氏病與泛發性路易體疾病(diffuse Lewy body disease)之混合癡呆、年齡相關之黃斑變性、帕金森氏病、澱粉狀蛋白血管病或其類似者。 The compound of the present invention has BACE1 inhibitory activity and is effective in treating and/or preventing a disease induced by the production, secretion or deposition of amyloid β protein, amelioration thereof and prevention of progression thereof, such as Alzheimer's Disease, Alzheimer's dementia, Alzheimer's type dementia, mild cognitive impairment (MCI), prodromal Alzheimer's disease (eg by MCI) for Alzheimer's disease, Down's syndrome, memory disorder, prion disease (Creutzfeldt-Jakob disease), hereditary cerebral hemorrhage with amyloidosis in the Netherlands, brain Amyloid angiopathy, other types of degenerative dementia, such as coexisting Alzheimer's disease and vascular dementia, dementia and Parkinson's disease, dementia and progressive supranuclear palsy, dementia and cortical basal ganglia degeneration, Az Hybridization of Dementia, age-related macular degeneration, Parkinson's disease, amyloid vascular disease, or the like, with Herm's disease and diffuse Lewy body disease.

此外，本發明化合物在預防具有阿茲海默癡呆症之風險(臨床前阿茲海默氏病)之無症狀患者中之進展中有效。 Furthermore, the compounds of the invention are effective in preventing progression in asymptomatic patients with a risk of Alzheimer's dementia (pre-clinical Alzheimer's disease).

「具有阿茲海默癡呆症風險之無症狀患者」包括認知及功能上正常，但具有阿茲海默氏病或典型年齡相關變化之潛在極早期徵兆(例如MRI之輕度白質高強度)，及/或具有如藉由低腦脊髓液Aβ1-42含量證實之澱粉狀蛋白沈積之跡象的個體。舉例而言，「具有阿茲海默癡呆症風險之無症狀患者」包括臨床癡呆評定量表(CDR)或臨床癡呆評定量表-日本版(CDR-J)之評分為0，及/或功能分期評定表(FAST)之階段為階段1或階段2之個體。 "Asymptomatic patients at risk of Alzheimer's dementia" include cognitively and functionally normal, but have potentially very early signs of Alzheimer's disease or typical age-related changes (eg, mild white matter high intensity of MRI), And/or individuals having signs of amyloid deposition as evidenced by low levels of cerebrospinal fluid A[beta] 1-42 . For example, "asymptomatic patients at risk of Alzheimer's dementia" include the Clinical Dementia Rating Scale (CDR) or the Clinical Dementia Rating Scale - Japanese version (CDR-J) with a score of 0, and/or function. The stage of the Staging Assessment Form (FAST) is the individual of Phase 1 or Phase 2.

本發明化合物不僅具有BACE1抑制活性，且亦具有作為藥物之益處。該化合物具有任何或所有以下優良特性。 The compounds of the present invention not only have BACE1 inhibitory activity, but also have the benefit of being a drug. The compound has any or all of the following excellent properties.

a)化合物對於諸如CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP3A4之CYP酶具有弱抑制活性。 a) The compounds have weak inhibitory activity against CYP enzymes such as CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4.

b)化合物顯示極佳藥物動力學概況，諸如高生物可用性或低清除率。 b) The compound shows an excellent pharmacokinetic profile, such as high bioavailability or low clearance.

c)化合物具有高代謝穩定性。 c) The compound has high metabolic stability.

d)化合物不在本說明書中所述之量測條件之濃度範圍內對諸如CYP3A4之CYP酶顯示不可逆抑制。 d) The compound exhibits irreversible inhibition of the CYP enzyme such as CYP3A4 within the concentration range of the measurement conditions described in the present specification.

e)化合物不顯示突變誘發。 e) The compound does not show mutation induction.

f)化合物對於心血管系統具有低風險。 f) Compounds have a low risk for the cardiovascular system.

g)化合物顯示高溶解度。 g) The compound shows high solubility.

h)化合物顯示高腦分佈。 h) The compound shows a high brain distribution.

i)化合物具有高口服吸收。 i) The compound has a high oral absorption.

j)化合物具有長半衰期。 j) The compound has a long half life.

k)化合物具有高蛋白非結合比。 k) The compound has a high protein non-binding ratio.

l)化合物在艾姆斯測試(Ames test)中為陰性的。 l) The compound was negative in the Ames test.

m)化合物具有超過BACE2之高BACE1選擇率。 m) The compound has a high BACE1 selectivity over BACE2.

由於本發明化合物對BACE1具有高抑制活性及/或對其他酶(例如BACE2)具有高選擇率，其可為具有減少之副作用之藥物。另外，由於化合物具有減少細胞系統中之澱粉狀蛋白β產生之高效應，特定言之具有減少大腦中之澱粉狀蛋白β產生之高效應，其可為極佳藥物。 另外，藉由將化合物轉化成具有適合之立體化學之光學活性化合物，化合物可為對副作用具有更寬安全限度之藥物。 Since the compound of the present invention has high inhibitory activity against BACE1 and/or has high selectivity for other enzymes such as BACE2, it may be a drug having reduced side effects. In addition, since the compound has a high effect of reducing the production of amyloid β in the cellular system, specifically, it has a high effect of reducing the production of amyloid β in the brain, which is an excellent drug. Additionally, by converting the compound to an optically active compound having suitable stereochemistry, the compound can be a drug with a broader safety margin for side effects.

當投與本發明之醫藥組合物時，其可經口或非經腸投與。用於經口投與之組合物可以常用劑型，諸如經口固體調配物(例如錠劑、散劑、顆粒劑、膠囊、丸劑、膜或其類似者)、經口液體調配物(例如懸浮液、乳液、酏劑、糖漿、檸檬劑、醑劑、芳族水、萃取液、煎劑、酊劑或其類似者)及其類似者投與，其可根據常用方法製備及投與。錠劑可為糖包衣錠、薄膜包衣錠、腸溶衣錠、緩釋錠、糖衣錠、舌下錠、頰內錠、咀嚼錠或口腔崩解錠。散劑及顆粒劑可為乾糖漿。 膠囊可為軟膠囊、微膠囊或緩釋膠囊。 When the pharmaceutical composition of the present invention is administered, it can be administered orally or parenterally. The composition for oral administration may be in a usual dosage form such as an oral solid preparation (for example, a tablet, a powder, a granule, a capsule, a pill, a film or the like), an oral liquid preparation (for example, a suspension, Emulsions, elixirs, syrups, lemons, elixirs, aromatic waters, extracts, decoctions, elixirs or the like), and the like, can be prepared and administered according to conventional methods. The tablet may be a sugar-coated tablet, a film-coated tablet, an enteric coated tablet, a sustained-release tablet, a sugar-coated tablet, a sublingual tablet, a buccal ingot, a chewable tablet or an orally disintegrating tablet. The powder and granules can be a dry syrup. The capsule may be a soft capsule, a microcapsule or a sustained release capsule.

用於非經腸投與之組合物可以常用非經腸劑型適當地投與，諸如經皮、皮下、靜脈內、動脈內、肌肉內、腹膜內、經黏膜、吸入、經鼻、經眼、耳內或經***投與及其類似者。在非經腸投與之情況下，可較佳投與通常使用之任何形式，諸如注射劑、滴劑、外部製劑 (例如滴眼劑、滴鼻劑、滴耳劑、氣溶膠、吸入劑、洗劑、輸注液、搽劑、漱口劑、灌腸劑、軟膏、硬膏劑、膠凍、乳膏劑、貼片、熱罨劑、外部散劑、栓劑或其類似者)及其類似者。注射劑可為乳液，其類型為O/W、W/O、O/W/O、W/O/W或其類似者。 Compositions for parenteral administration may be suitably administered in parenteral dosage forms such as transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, transocular, Intra- or vaginal administration and the like. In the case of parenteral administration, it may be preferably administered in any form conventionally used, such as injections, drops, external preparations. (eg eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, infusions, tinctures, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, A chelating agent, an external powder, a suppository or the like) and the like. The injection may be an emulsion of the type O/W, W/O, O/W/O, W/O/W or the like.

由於口服劑型之高經口吸收性，本發明化合物可較佳以口服劑型投與。 Due to the high oral absorbability of the oral dosage form, the compounds of the invention may preferably be administered in an oral dosage form.

醫藥組合物可藉由在必要時混合適合於與有效量之本發明化合物調配的用於藥物之各種添加劑，諸如賦形劑、黏合劑、崩解劑及潤滑劑而調配。此外，醫藥組合物可藉由恰當地改變本發明化合物、調配物及/或各種醫藥添加劑之有效量而用於小兒患者、老年患者、嚴重病例或手術。小兒醫藥組合物較佳向12或15歲以下之患者投與。另外，小兒醫藥組合物可向出生後27天齡以下、出生後28天至23月齡、2至11歲、12至16歲或18歲患者投與。老年醫藥組合物較佳向65歲或65歲以上之患者投與。 The pharmaceutical composition can be formulated by mixing, if necessary, various additives for the drug, such as excipients, binders, disintegrants and lubricants, which are suitable for formulation with an effective amount of the compound of the present invention. Furthermore, the pharmaceutical compositions can be used in pediatric patients, elderly patients, severe cases or surgery by appropriately varying the effective amount of the compounds, formulations and/or various pharmaceutical additives of the invention. The pediatric pharmaceutical composition is preferably administered to a patient under 12 or 15 years of age. In addition, the pediatric pharmaceutical composition can be administered to patients under 27 days of age, 28 days to 23 months after birth, 2 to 11 years old, 12 to 16 years old, or 18 years old. Geriatric pharmaceutical compositions are preferably administered to patients 65 years of age or older.

本發明之醫藥組合物之劑量應考慮到患者之年齡及體重、疾病類型及程度、投與途徑及其類似者而確定。用於成人之常用口服劑量在0.05至100毫克/公斤/日範圍內且較佳0.1至10毫克/公斤/日。對於非經腸投與，劑量隨投與途徑高度變化且常用劑量在0.005至10毫克/公斤/日範圍內且較佳0.01至1毫克/公斤/日。劑量可每日投與一次或若干次。 The dosage of the pharmaceutical composition of the present invention should be determined in consideration of the age and weight of the patient, the type and extent of the disease, the route of administration, and the like. Oral oral doses for use in adults range from 0.05 to 100 mg/kg/day and preferably from 0.1 to 10 mg/kg/day. For parenteral administration, the dosage will vary widely with the route of administration and the usual dosage will be in the range of 0.005 to 10 mg/kg/day and preferably 0.01 to 1 mg/kg/day. The dose can be administered once or several times a day.

出於執行化合物之活性或減少化合物之藥物量或其類似者之目的，本發明化合物可與用於治療阿茲海默氏病、阿茲海默癡呆症或其類似者之其他藥物，諸如乙醯膽鹼酯酶抑制劑(在下文中稱為伴隨藥物)組合使用。在此狀況下，投與本發明化合物及伴隨藥物之時序不受限且可向個體同時或以有規律間隔投與此等者。此外，本發明化合物及伴隨藥物可以含有各活性成分之兩種不同組合物或含有兩種活性 成分之單一組合物形式投與。 The compound of the present invention may be used in combination with other drugs, such as B, for the treatment of Alzheimer's disease, Alzheimer's dementia or the like for the purpose of performing the activity of the compound or reducing the amount of the drug of the compound or the like. A cholinesterase inhibitor (hereinafter referred to as a concomitant drug) is used in combination. In this case, the timing of administration of the compound of the present invention and the concomitant drug is not limited and may be administered to the individual simultaneously or at regular intervals. Furthermore, the compounds of the invention and concomitant drugs may contain two different compositions of the active ingredients or contain two activities. A single composition of the ingredients is administered.

伴隨藥物之劑量可基於臨床上使用之劑量適當地選擇。此外，本發明化合物及伴隨藥物之混合比可考慮到投與之個體、投與途徑、目標疾病、症狀、組合等適當地選擇。舉例而言，當投與之個體為人類時，伴隨藥物可在相對於1重量份本發明化合物0.01至100重量份之範圍內使用。 The dose accompanying the drug can be appropriately selected based on the dose used clinically. Further, the mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected in consideration of the individual to be administered, the administration route, the target disease, the symptom, the combination, and the like. For example, when the individual to be administered is a human, the concomitant drug can be used in an amount of 0.01 to 100 parts by weight relative to 1 part by weight of the compound of the present invention.

伴隨藥物之實例為鹽酸多奈哌齊(Donepezil)、他可林(Tacrine)、加蘭他敏(Galanthamine)、雷斯替明(Rivastigmine)、紮那哌齊(Zanapezil)、美金剛(Memantine)及長春西汀(Vinpocetine)。 Examples of concomitant drugs are Donepezil hydrochloride, Tacrine, Galantamine, Rivastigmine, Zanapezil, Memantine, and Vinci. Vinpocetine.

[實例] [Example]

以下實例及測試實例更詳細地說明本發明，但本發明不限於此等實例。 The following examples and test examples illustrate the invention in more detail, but the invention is not limited to such examples.

在實例中，各縮寫之含義如下： In the examples, the meanings of the abbreviations are as follows:

1H NMR光譜記錄於Bruker Advance 400MHz光譜儀上，化學位移相對於四甲基矽烷或殘留溶劑峰(CDCl3=7.26ppm，DMSO-d6=2.50ppm)報導。 1 H NMR spectra were recorded on a Bruker Advance 400 MHz spectrometer with chemical shifts reported relative to tetramethyl decane or residual solvent peaks (CDCl 3 = 7.26 ppm, DMSO-d 6 = 2.50 ppm).

分析型LC/MS(ESI正性或負性，滯留時間(RT))資料在以下條件下記錄於Shimadzu UFLC或Waters UPLC系統上：管柱：Shim-pack XR-ODS(2.2μm，內徑50×3.0mm)(Shimadzu) Analytical LC/MS (ESI positive or negative, residence time (RT)) data were recorded on a Shimadzu UFLC or Waters UPLC system under the following conditions: Column: Shim-pack XR-ODS (2.2 μm, internal diameter 50) ×3.0mm)(Shimadzu)

流動速率：1.6mL/min Flow rate: 1.6mL/min

管柱烘箱：50℃ Column oven: 50 ° C

UV偵測波長：254nm UV detection wavelength: 254nm

移動相：[A]含0.1%甲酸之水溶液；[B]含0.1%甲酸之乙腈溶液 Mobile phase: [A] aqueous solution containing 0.1% formic acid; [B] acetonitrile solution containing 0.1% formic acid

梯度：線性梯度，10%至100%溶劑[B]，持續3分鐘及100%溶劑[B]，持續1分鐘 Gradient: linear gradient, 10% to 100% solvent [B] for 3 minutes and 100% solvent [B] for 1 minute

實例1 合成化合物I-5 Example 1 Synthesis of Compound I-5

步驟1 step 1

將鋅(1.40g，21.4mmol)於THF(80ml)中之攪拌懸浮液中加熱至 回流。向懸浮液中添加化合物1-1(8.46g，19.4mmol)於THF(20ml)中之溶液及2-溴-2-氟乙酸乙酯(3.95g，21.4mmol)於THF(10ml)中之溶液。在相同溫度下攪拌3h之後，用NH4Cl飽和水溶液處理反應混合物且用AcOEt萃取水層。用鹽水洗滌合併之有機層，經Na2SO4乾燥，過濾且濃縮。將粗產物添加至矽膠管柱且用己烷/EtOAc 25%溶離。 蒸發收集之溶離份，獲得呈褐色油狀之化合物1-2(5.76g，10.6mmol，55%)。 The stirred suspension of zinc (1.40 g, 21.4 mmol) in THF (80 mL) was heated to reflux. A solution of the compound 1-1 (8.46 g, 19.4 mmol) in THF (20 mL) and EtOAc (EtOAc m. . After stirring at the same temperature for 3h, treated with saturated aqueous NH 4 Cl the reaction mixture and the aqueous layer was extracted with AcOEt. , Dried combined organic layers were washed with brine, Na 2 SO 4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with hexane /EtOAc 25%. The collected fractions were evaporated to give compound 1-2 (5.76 g, 10.6 mmol, 55%).

1H-NMR(400MHz,CDCl3)δ：0.84-0.89(m,6H),0.94-0.98(m,9H),1.24(s,9H),1.29(t,J=7.2Hz,3H),1.96(s,3H),4.26(m,2H),5.16(s,1H),5.34(d,J=46.4Hz,1H),7.37(d,J=2.6Hz,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 0.84-0.89 (m, 6H), 0.94-0.98 (m, 9H), 1.24 (s, 9H), 1.29 (t, J = 7.2Hz, 3H), 1.96 (s, 3H), 4.26 (m, 2H), 5.16 (s, 1H), 5.34 (d, J = 46.4 Hz, 1H), 7.37 (d, J = 2.6 Hz, 1H).

步驟2 Step 2

將KF(1.24g，21.3mmol)添加至化合物1-2(5.76g，10.6mmol)及AcOH(1.22mL，21.3mmol)於THF(30ml)中之溶液中。添加DMF(30ml)，且在室溫下攪拌混合物。在相同溫度下攪拌2.5h之後，用NaHCO3飽和水溶液處理反應混合物且用AcOEt萃取水層。用鹽水洗滌合併之有機層，經Na2SO4乾燥，過濾且濃縮。將粗產物添加至矽膠管柱且用己烷/EtOAc 30%至50%溶離。蒸發收集之溶離份，獲得呈褐色油狀之化合物1-3(4.01g，9.38mmol，88%)。 KF (1.24 g, 21.3 mmol) was added to a solution of compound 1-2 (5.76 g, 10.6 mmol) and AcOH (1.22 mL, 21.3 mmol) in THF (30 mL). DMF (30 ml) was added, and the mixture was stirred at room temperature. After stirring for 2.5h at the same temperature, the mixture was treated with saturated aqueous NaHCO 3 and the aqueous layer was extracted reaction with AcOEt. , Dried combined organic layers were washed with brine, Na 2 SO 4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with hexanes/EtOAc 30% to 50%. The collected fractions were evaporated to give compound 1-3 (4.01 g, 9.38 mmol, 88%).

1H-NMR(400MHz,CDCl3)δ：1.25(s,9H),1.30(t,J=7.2Hz,3H),1.97(s,3H),4.27(m,2H),5.14(s,1H),5.35(d,J=46.4Hz,1H),7.29(dd,J=10.8,8.4Hz,1H),7.45(dd,J=8.4,2.9Hz,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.25 (s, 9H), 1.30 (t, J = 7.2Hz, 3H), 1.97 (s, 3H), 4.27 (m, 2H), 5.14 (s, 1H ), 5.35 (d, J = 46.4 Hz, 1H), 7.29 (dd, J = 10.8, 8.4 Hz, 1H), 7.45 (dd, J = 8.4, 2.9 Hz, 1H).

步驟3 Step 3

在-78℃下向化合物1-3(3.94g，9.22mmol)於CH2Cl2(40ml)中之溶液中添加1.02mol/L DIBAL(27.1ml，27.7mmol)。在相同溫度下攪拌15分鐘之後，用羅謝爾鹽(Rochelle's salt)飽和水溶液處理混合物且攪拌2.5h。用AcOEt萃取水層，且用鹽水洗滌合併之有機層，經 Na2SO4乾燥且過濾。於真空中濃縮濾液，得到呈黃色非晶形形式之化合物1-4，其不經純化即用於下一步驟。 Was added 1.02mol / L DIBAL (27.1ml, 27.7mmol ) in the direction (3.94g, 9.22mmol) in CH 2 Cl 2 (40ml) solution of the compound 1-3 at -78 ℃. After stirring at the same temperature for 15 minutes, the mixture was treated with a saturated aqueous solution of Rochelle's salt and stirred for 2.5 h. The aqueous layer was extracted with AcOEt, and the organic layers were combined and washed with the brine, dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to afford compound 1-4 as a yellow crystal.

在室溫下向溴化甲基三苯基鏻(8.23g，23.0mmol)於甲苯(85ml)中之溶液中添加THF(21.2ml，21.2mmol)中之1.00mol/L t-BuOK溶液。在相同溫度下攪拌1h之後，在0℃下添加化合物1-4於甲苯(30ml)中之溶液。在室溫下攪拌90分鐘之後，用NH4Cl飽和水溶液處理反應混合物且用AcOEt萃取水層。用鹽水洗滌合併之有機層，經Na2SO4乾燥，過濾且濃縮。將粗產物添加至矽膠管柱且用己烷/EtOAc 10%至50%溶離。蒸發收集之溶離份，獲得呈白色非晶形形式之化合物1-5(1.57g，4.12mmol，45%)。 A solution of 1.00 mol/L t-BuOK in THF (21.2 ml, 21.2 mmol) was added to a solution of methyltriphenylphosphonium bromide (8.23 g, 23.0 mmol) in toluene (85 ml). After stirring at the same temperature for 1 h, a solution of compound 1-4 in toluene (30 ml) was added at 0 °C. After stirring at room temperature for 90 minutes, treated with saturated NH 4 Cl solution and the reaction mixture was treated aqueous layer was extracted with AcOEt. , Dried combined organic layers were washed with brine, Na 2 SO 4, filtered and concentrated. The crude product was added to a silica gel column and was dissolved with hexanes/EtOAc 10% to 50%. The collected fractions were evaporated to give compound 1-5 (1.57 g, 4.12 mmol, 45%).

1H-NMR(400MHz,CDCl3)δ：1.24(s,9H),1.85(t,J=1.8Hz,3H),5.11(s,1H),5.17-5.32(m,2H),5.34(d,J=1.1Hz,1H),5.91-6.04(m,1H),7.29(dd,J=10.7,8.5Hz,1H),7.43(dd,J=3.0,8.5Hz,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.24 (s, 9H), 1.85 (t, J = 1.8Hz, 3H), 5.11 (s, 1H), 5.17-5.32 (m, 2H), 5.34 (d , J = 1.1 Hz, 1H), 5.91-6.04 (m, 1H), 7.29 (dd, J = 10.7, 8.5 Hz, 1H), 7.43 (dd, J = 3.0, 8.5 Hz, 1H).

步驟4 Step 4

在室溫下向化合物1-5(1.57g，4.12mmol)於MeOH(16ml)中之溶液中添加二烷(1.54ml，6.18mmol)中之4mol/L HCl。在相同溫度下攪拌30分鐘之後，用NaHCO3水溶液處理反應混合物且用AcOEt萃取水層。用H2O及鹽水洗滌合併之有機層，經Na2SO4乾燥，過濾且濃縮，得到化合物1-6，其不經純化即用於下一步驟。 To a solution of compound 1-5 (1.57 g, 4.12 mmol) in MeOH (16 mL) 4 mol/L HCl in alkane (1.54 ml, 6.18 mmol). After stirring at the same temperature for 30 minutes, the reaction mixture was treated with aqueous NaHCO 3 and the aqueous layer was extracted with AcOEt. , 2 O and dried combined organic layers were washed with brine H over Na 2 SO 4, filtered and concentrated to give compound 1-6, which was used without purification in the next step.

在0℃下向1-6於CH2Cl2(11ml)中之溶液中添加異硫氰酸苯甲醯酯(0.848ml，2.58mmol)。在室溫下攪拌30分鐘之後，濃縮反應混合物，且將所得殘餘物添加至矽膠管柱中且用己烷/EtOAc 0%至25%溶離。蒸發收集之溶離份，獲得呈黃色油狀之化合物1-7(1.81g，4.12mmol，定量)。 To a solution of 1-6 in CH 2 Cl 2 (11 ml) was added benzyl thiocyanate (0.848 ml, 2.58 mmol). After stirring at room temperature for 30 minutes, the reaction mixture was concentrated, and the obtained residue was added to a silica gel column and eluted from hexane / EtOAc 0% to 25%. The collected fractions were evaporated to give compound 1-7 (1.81 g, 4.21.

1H-NMR(400MHz,CDCl3)δ：2.12(d,J=0.9Hz,3H),5.43-5.61 (m,3H),5.90-6.03(m,1H),7.19(dd,J=10.6,8.5Hz,1H),7.40(dd,J=8.5,3.0Hz,1H),7.52(t,J=7.7Hz,2H),7.63(t,J=7.7Hz,1H),7.85(d,J=7.7Hz,2H),8.83(s,1H),11.53(s,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 2.12 (d, J = 0.9Hz, 3H), 5.43-5.61 (m, 3H), 5.90-6.03 (m, 1H), 7.19 (dd, J = 10.6, 8.5 Hz, 1H), 7.40 (dd, J = 8.5, 3.0 Hz, 1H), 7.52 (t, J = 7.7 Hz, 2H), 7.63 (t, J = 7.7 Hz, 1H), 7.85 (d, J = 7.7 Hz, 2H), 8.83 (s, 1H), 11.53 (s, 1H).

步驟5 Step 5

在0℃下向碘(2.09g，8.24mmol)於MeCN(40ml)中之溶液中添加MeCN(14ml)中之化合物1-7(1.81g，4.12mmol)。在相同溫度下攪拌20分鐘之後，用NaHCO3及Na2S2O3水溶液處理反應混合物。用AcOEt萃取水層。用鹽水洗滌合併之有機層，經Na2SO4乾燥，過濾且濃縮。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至35%溶離。 蒸發收集之溶離份，獲得呈黃色非晶形形式之化合物1-8(2.18g，3.85mmol，94%)。 To a solution of iodine (2.09 g, 8.24 mmol) in MeCN (40 mL), EtOAc (EtOAc) After stirring at the same temperature for 20 minutes, the reaction mixture was treated with aqueous NaHCO 3 and Na 2 S 2 O 3 . The aqueous layer was extracted with AcOEt. , Dried combined organic layers were washed with brine, Na 2 SO 4, filtered and concentrated. The crude product was added to a silica gel column and was dissolved with hexane / EtOAc 0% to 35%. The collected fractions were evaporated to give compound 1-8 (2.18 g, 3.85 mmol, 94%).

1H-NMR(400MHz,CDCl3)δ：1.90(s,3H),3.29(dd,J=10.4,5.0Hz,1H),3.58(t,J=10.4Hz,1H),3.94-3.79(m,1H),5.75(d,J=47.3Hz,1H),7.52-7.32(m,6H),8.16(d,J=6.9Hz,2H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.90 (s, 3H), 3.29 (dd, J = 10.4,5.0Hz, 1H), 3.58 (t, J = 10.4Hz, 1H), 3.94-3.79 (m , 1H), 5.75 (d, J = 47.3 Hz, 1H), 7.52 - 7.32 (m, 6H), 8.16 (d, J = 6.9 Hz, 2H).

步驟6 Step 6

在室溫下向化合物1-8(1.52g，2.68mmol)於DMSO(1ml)及H2O(0.1ml)中之溶液中添加AgBF4(1.05g，5.37mmol)。在相同溫度下攪拌2h之後，用NaHCO3水溶液處理反應混合物。用AcOEt萃取水層，且經Na2SO4乾燥有機層，過濾且濃縮。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至50%溶離。蒸發收集之溶離份，獲得呈白色非晶形形式之化合物1-9(684mg，1.50mmol，56%)。 Was added AgBF 4 (1.05g, 5.37mmol) in the direction (1ml) and H 2 O (0.1ml) solution of compound 1-8 (1.52g, 2.68mmol) in DMSO at rt. After stirring for 2h at the same temperature, the mixture was treated with aqueous NaHCO 3 solution the reaction. The aqueous layer was extracted with AcOEt, and organic layer and dried over Na 2 SO 4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with hexanes/EtOAc from 0% to 50%. The collected fractions were evaporated to give compound 1-9 (684 mg, 1.50 mmol, 56%).

1H-NMR(400MHz,CDCl3)δ：1.88(s,3H),3.74-3.94(m,2H),4.14(dd,J=7.3,2.8Hz,1H),5.67(d,J=47.2Hz,1H),7.31-7.51(m,6H),8.18(d,J=7.3Hz,2H)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.88 (s, 3H), 3.74-3.94 (m, 2H), 4.14 (dd, J = 7.3, 2.8 Hz, 1H), 5.67 (d, J = 47.2 Hz) , 1H), 7.31 - 7.51 (m, 6H), 8.18 (d, J = 7.3 Hz, 2H).

步驟7 Step 7

在0℃下向化合物1-9(325mg，0.712mmol)於DMF(4ml)中之溶 液中添加咪唑(194mg，2.85mmol)及TBSCl(215mg，1.42mmol)。 在室溫下攪拌20分鐘之後，用H2O處理反應混合物。用AcOEt萃取水層，且經Na2SO4乾燥有機層，過濾且濃縮。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至30%溶離。蒸發收集之溶離份，獲得呈白色非晶形形式之化合物1-10(384mg，0.673mmol，95%)。 To a solution of compound 1-9 (325 mg, 0.712 mmol) in EtOAc (4 mL). After stirring at room temperature for 20 minutes, the reaction mixture was treated with H 2 O. The aqueous layer was extracted with AcOEt, and organic layer and dried over Na 2 SO 4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with hexane / EtOAc from 0% to 30%. The collected fractions were evaporated to give compound 1-10 (384 mg, 0.673 mmol, 95%) as white white.

1H-NMR(400MHz,CDCl3)δ：0.11(s,3H),0.12(s,3H),0.92(s,9H),1.87(s,3H),3.64-3.69(m,1H),3.72-3.79(m,1H),4.03-4.09(m,1H),5.60(dd,J=46.9,1.3Hz,1H),7.50-7.30(m,5H),8.20(d,J=7.3Hz,2H)。 1 H-NMR (400MHz, CDCl 3) δ: 0.11 (s, 3H), 0.12 (s, 3H), 0.92 (s, 9H), 1.87 (s, 3H), 3.64-3.69 (m, 1H), 3.72 -3.79 (m, 1H), 4.03-4.09 (m, 1H), 5.60 (dd, J = 46.9, 1.3 Hz, 1H), 7.50-7.30 (m, 5H), 8.20 (d, J = 7.3 Hz, 2H) ).

步驟8 Step 8

在室溫下向化合物1-10(384mg，0.673mmol)於THF(4ml)中之溶液中添加Boc2O(0.234ml，1.01mmol)及DMAP(32.9mg，0.269mmol)。在相同溫度下攪拌20分鐘之後，在真空下濃縮混合物。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至30%溶離。蒸發收集之溶離份，獲得呈白色非晶形形式之化合物1-11(451mg，0.672mmol，定量)。 Add a solution of compound 1-10 (384mg, 0.673mmol) in THF (4ml) in a solution of Boc 2 O (0.234ml, 1.01mmol) and DMAP (32.9mg, 0.269mmol). After stirring at the same temperature for 20 minutes, the mixture was concentrated under vacuum. The crude product was added to a silica gel column and was eluted with hexane / EtOAc from 0% to 30%. The collected fractions were evaporated to give Compound 1-11 (451 mg, 0.672 mmol, quantitative) as a white amorphous form.

1H-NMR(400MHz,CDCl3)δ：0.08(s,3H),0.09(s,3H),0.90(s,9H),1.39(s,9H),1.62(d,J=2.4Hz,3H),3.71-3.76(m,1H),3.89(dt,J=30.3,7.7Hz,1H),4.06(dd,J=9.8,7.7Hz,1H),5.33(dd,J=47.4,1.6Hz,1H),7.19(t,J=9.2Hz,1H),7.33-7.40(m,3H),7.48(t,J=7.3Hz,1H),7.76(d,J=7.3Hz,2H)。 1 H-NMR (400MHz, CDCl 3) δ: 0.08 (s, 3H), 0.09 (s, 3H), 0.90 (s, 9H), 1.39 (s, 9H), 1.62 (d, J = 2.4Hz, 3H ), 3.71-3.76 (m, 1H), 3.89 (dt, J = 30.3, 7.7 Hz, 1H), 4.06 (dd, J = 9.8, 7.7 Hz, 1H), 5.33 (dd, J = 47.4, 1.6 Hz, 1H), 7.19 (t, J = 9.2 Hz, 1H), 7.33-7.40 (m, 3H), 7.48 (t, J = 7.3 Hz, 1H), 7.76 (d, J = 7.3 Hz, 2H).

步驟9 Step 9

在室溫下向化合物1-11(451mg，0.672mmol)於THF(2ml)、MeOH(2ml)及H2O(2ml)中之溶液中添加K2CO3(279mg，2.02mmol)。在50℃下攪拌2h之後，用H2O處理反應混合物。用AcOEt萃取水層，且經Na2SO4乾燥有機層，過濾且濃縮。將粗產物添加至矽膠 管柱中且用己烷/EtOAc 0%至30%溶離。蒸發收集之溶離份，獲得呈白色非晶形形式之化合物1-12(346mg，0.611mmol，91%)。 In the solution of compound 1-11 (451mg, 0.672mmol) in THF (2ml), MeOH (2ml ) and H 2 O (2ml) at room temperature was added K 2 CO 3 (279mg, 2.02mmol ). After stirring at 50 ° C for 2 h, the reaction mixture was treated with H 2 O. The aqueous layer was extracted with AcOEt, and organic layer and dried over Na 2 SO 4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with hexane / EtOAc from 0% to 30%. The collected fractions were evaporated to give compound 1-12 (346 mg, 0.611 mmol, 91%).

1H-NMR(400MHz,CDCl3)δ：0.07(s,3H),0.08(s,3H),0.89(s,9H),1.50(s,9H),1.79(s,3H),3.49-3.70(m,2H),3.99(t,J=9.0Hz,1H),5.53(d,J=47.2Hz,1H),7.30(t,J=9.4Hz,1H),7.45-7.41(m,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 0.07 (s, 3H), 0.08 (s, 3H), 0.89 (s, 9H), 1.50 (s, 9H), 1.79 (s, 3H), 3.49-3.70 (m, 2H), 3.99 (t, J = 9.0 Hz, 1H), 5.53 (d, J = 47.2 Hz, 1H), 7.30 (t, J = 9.4 Hz, 1H), 7.45 - 7.41 (m, 1H) .

步驟10 Step 10

在室溫下向化合物1-12(346mg，0.611mmol)於THF(4ml)中之溶液中添加Boc2O(0.213ml，0.916mmol)及DMAP(29.8mg，0.244mmol)。在相同溫度下攪拌30分鐘之後，在真空下濃縮混合物。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至30%溶離。蒸發收集之溶離份，獲得呈白色固體狀之化合物1-13(370mg，0.555mmol，91%)。 Add a solution of compound 1-12 (346mg, 0.611mmol) in THF (4ml) in a solution of Boc 2 O (0.213ml, 0.916mmol) and DMAP (29.8mg, 0.244mmol). After stirring at the same temperature for 30 minutes, the mixture was concentrated under vacuum. The crude product was added to a silica gel column and was eluted with hexane / EtOAc from 0% to 30%. The collected fractions were evaporated to give compound 1-13 (370 mg, 0.555

1H-NMR(400MHz,CDCl3)δ：0.11(s,3H),0.11(s,3H),0.92(s,9H),1.42(s,18H),1.82(d,J=1.9Hz,3H),3.73-3.79(m,1H),3.97-4.15(m,2H),5.45(d,J=47.7Hz,1H),7.25-7.31(m,1H),7.39(dd,J=8.4,3.0Hz,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 0.11 (s, 3H), 0.11 (s, 3H), 0.92 (s, 9H), 1.42 (s, 18H), 1.82 (d, J = 1.9Hz, 3H ), 3.73 - 3.79 (m, 1H), 3.97 - 4.15 (m, 2H), 5.45 (d, J = 47.7 Hz, 1H), 7.25 - 7.31 (m, 1H), 7.39 (dd, J = 8.4, 3.0) Hz, 1H).

步驟11 Step 11

在室溫下向化合物1-13(400mg，0.600mmol)於THF(8ml)中之溶液中添加AcOH(0.0510ml，0.900mmol)及TBAF(THF中之1.00mol/L溶液，1.80ml，1.80mmol)。在相同溫度下攪拌1h之後，用H2O處理反應混合物。用AcOEt萃取水層，且經Na2SO4乾燥有機層，過濾且濃縮。將粗產物添加至矽膠管柱且用己烷/EtOAc 10%至50%溶離。蒸發收集之溶離份，獲得呈白色非晶形形式之化合物1-14(323mg，0.585mmol，98%)。 Add AcOH (0.0510 ml, 0.900 mmol) and TBAF (1.00 mol/L solution in THF, 1.80 ml, 1.80 mmol) to a solution of compound 1-13 (400 mg, 0.600 mmol) in THF (8 mL). ). After stirring at the same temperature for 1 h, the reaction mixture was treated with H 2 O. The aqueous layer was extracted with AcOEt, and organic layer and dried over Na 2 SO 4, filtered and concentrated. The crude product was added to a silica gel column and was dissolved with hexanes/EtOAc 10% to 50%. The collected fractions were evaporated to give compound 1-14 (323 mg, 0.585 mmol, 98%) as white white.

1H-NMR(400MHz,CDCl3)δ：1.43(s,9H),1.84(s,3H),3.84-3.95(m,1H),4.04-4.19(m,2H),5.51(d,J=47.4Hz,1H),7.27-7.42(m,2H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.43 (s, 9H), 1.84 (s, 3H), 3.84-3.95 (m, 1H), 4.04-4.19 (m, 2H), 5.51 (d, J = 47.4 Hz, 1H), 7.27-7.42 (m, 2H).

步驟12 Step 12

在-78℃下向化合物1-14(323mg，0.585mmol)於CH2Cl2(10ml)中之溶液中添加DAST(0.257ml，1.75mmol)。在室溫下攪拌40分鐘之後，用NaHCO3水溶液處理反應混合物。用AcOEt萃取水層，且經Na2SO4乾燥有機層，過濾且濃縮。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至30%溶離。蒸發收集之溶離份，獲得呈白色非晶形形式之化合物5-15(310mg，0.559mmol，96%)。 Add DAST (0.257ml, 1.75mmol) of compound 1-14 (323mg, 0.585mmol) in CH 2 Cl 2 (10ml) in the solution at -78 ℃. After stirring at room temperature for 40 minutes, the mixture reaction was treated with aqueous NaHCO 3. The aqueous layer was extracted with AcOEt, and organic layer and dried over Na 2 SO 4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with hexane / EtOAc from 0% to 30%. The collected fractions were evaporated to give compound 5-15 (310 mg, 0.559 mmol, 96%) as white white.

1H-NMR(400MHz,CDCl3)δ：1.42(s,18H),1.85(d,J=2.1Hz,3H),4.28-4.61(m,2H),4.90(dt,J=46.6,8.4Hz,1H),5.50(dd,J=47.1,1.8Hz,1H),7.30(t,J=9.0Hz,1H),7.42(dd,J=9.0,3.1Hz,1H)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.42 (s, 18H), 1.85 (d, J = 2.1 Hz, 3H), 4.28 - 4.61 (m, 2H), 4.90 (dt, J = 46.6, 8.4 Hz , 1H), 5.50 (dd, J = 47.1, 1.8 Hz, 1H), 7.30 (t, J = 9.0 Hz, 1H), 7.42 (dd, J = 9.0, 3.1 Hz, 1H).

步驟13 Step 13

在室溫下攪拌Pd2(dba)3(11.6mg，0.0130mmol)及氧雜蒽膦(21.9mg，0.0380mmol)於二烷(1ml)中之脫氣混合物1h。向此混合物中添加二烷(3ml)、化合物1-15(70.0mg，0.126mmol)、5-(氟甲氧基)吡-2-甲醯胺(25.9mg，0.152mmol)及碳酸銫(49.4mg，0.152mmol)。在90℃下攪拌6h之後，向反應混合物中進一步添加5-(氟甲氧基)吡-2-甲醯胺(25.9mg，0.152mmol)及碳酸銫(49.4mg，0.152mmol)。在再攪拌11h之後，用檸檬酸水溶液處理反應混合物且過濾。用AcOEt萃取水層，且經Na2SO4乾燥有機層，過濾且濃縮。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至35%溶離。蒸發收集之溶離份，獲得呈黃色油狀之化合物1-16(55.0mg，0.0850mmol，68%)。 Pd 2 (dba) 3 (11.6 mg, 0.0130 mmol) and oxaphosphonium (21.9 mg, 0.0380 mmol) were stirred at room temperature. Degassed mixture in alkane (1 ml) 1 h. Add two to this mixture Alkane (3ml), compound 1-15 (70.0mg, 0.126mmol), 5-(fluoromethoxy)pyridinium 2-Protonamine (25.9 mg, 0.152 mmol) and cesium carbonate (49.4 mg, 0.152 mmol). After stirring at 90 ° C for 6 h, further addition of 5-(fluoromethoxy)pyrene to the reaction mixture 2-Protonamine (25.9 mg, 0.152 mmol) and cesium carbonate (49.4 mg, 0.152 mmol). After stirring for an additional 11 h, the reaction mixture was treated with aqueous citric acid and filtered. The aqueous layer was extracted with AcOEt, and organic layer and dried over Na 2 SO 4, filtered and concentrated. The crude product was added to a silica gel column and was dissolved with hexane / EtOAc 0% to 35%. The collected fractions were evaporated to give compound 1-16 (55.0 mg, EtOAc.

1H-NMR(400MHz,CDCl3)δ：1.48(s,18H),1.89(s,3H),3.99-4.11(m,1H),4.37-4.53(m,1H),4.85(dt,J=47.0,8.8Hz,1H),5.49(d,J=48.4Hz,1H),6.16(d,J=50.9Hz,2H),7.52(t,J=9.3Hz,1H),8.31(s,1H),8.39(dd,J=9.3,3.0Hz,1H),9.09(s,1H),10.01(s,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.48 (s, 18H), 1.89 (s, 3H), 3.99-4.11 (m, 1H), 4.37-4.53 (m, 1H), 4.85 (dt, J = 47.0, 8.8 Hz, 1H), 5.49 (d, J = 48.4 Hz, 1H), 6.16 (d, J = 50.9 Hz, 2H), 7.52 (t, J = 9.3 Hz, 1H), 8.31 (s, 1H) , 8.39 (dd, J = 9.3, 3.0 Hz, 1H), 9.09 (s, 1H), 10.01 (s, 1H).

步驟14 Step 14

在室溫下攪拌化合物1-16(55.0mg，0.0850mmol)於甲酸(0.982ml)中之溶液22h。用K2CO3水溶液處理反應混合物。用AcOEt萃取水層，且經Na2SO4乾燥有機層，過濾且濃縮，獲得呈茶色固體狀之化合物I-5(24.0mg，0.0540mmol，63%)。 A solution of compound 1-16 (55.0 mg, 0.0850 mmol) in formic acid (0.982 ml) was stirred for 22h. The reaction mixture was treated with aq. K 2 CO 3 . The aqueous layer was extracted with AcOEt, and organic layer and dried over Na 2 SO 4, filtered and concentrated to give a brown solid of Compound I-5 (24.0mg, 0.0540mmol, 63%).

實例2 合成化合物I-7 Example 2 Synthesis of Compound I-7

步驟1 step 1

在-78℃下向化合物2-1(2.00g，8.29mmol)於THF(20ml)中之溶液中添加LHMDS(THF中之1.00mmol/L，16.6mL，16.6mmol)之溶液。在攪拌40分鐘之後，添加1,1,1-三氟丙-2-酮(1.48ml，16.6mmol)於THF(5ml)中之溶液且在相同溫度下攪拌混合物20分鐘。用NH4Cl水溶液處理反應混合物。用AcOEt萃取水層，且經Na2SO4乾燥有機層，過濾且濃縮。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至20%溶離。蒸發收集之溶離份，獲得呈黃色固體狀之化合物2-2(1.79g，5.07mmol，61%)。 A solution of LHMDS (1.00 mmol/L in THF, 16.6 mL, 16.6 mmol) was added to a solution of Compound 2-1 (2.00 g, 8.29 mmol) in THF (20 mL). After stirring for 40 minutes, a solution of 1,1,1-trifluoropropan-2-one (1.48 ml, 16.6 mmol) in THF (5 ml) was added and the mixture was stirred at the same temperature for 20 min. The reaction mixture was treated with aqueous NH 4 Cl. The aqueous layer was extracted with AcOEt, and organic layer and dried over Na 2 SO 4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with hexanes/EtOAc from 0% to 20%. The collected fractions were evaporated to give compound 2-2 (1.

1H-NMR(400MHz,CDCl3)δ：1.04(s,3H),1.39(s,9H),3.45(d,J=12.7Hz,1H),3.80(d,J=12.7Hz,1H),6.31(s,1H),7.15(dd,J=11.4,8.3Hz,1H),7.24(t,J=8.3Hz,1H),7.55-7.44(m,2H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.04 (s, 3H), 1.39 (s, 9H), 3.45 (d, J = 12.7Hz, 1H), 3.80 (d, J = 12.7Hz, 1H), 6.31 (s, 1H), 7.15 (dd, J = 11.4, 8.3 Hz, 1H), 7.24 (t, J = 8.3 Hz, 1H), 7.55-7.44 (m, 2H).

步驟2 Step 2

在室溫下向化合物2-2(896mg，2.54mmol)於MeOH(12ml)中之溶液中添加H2O(6.34ml，12.7mmol)中之4mol/L HCl。在相同溫度下攪拌1h之後，用NaHCO3水溶液處理反應混合物，且用AcOEt萃取水層。用H2O及鹽水洗滌合併之有機層，經Na2SO4乾燥，過濾且濃縮。將粗產物添加至矽膠管柱且用己烷/EtOAc 20%溶離。蒸發收集之溶離份，獲得呈白色固體狀之化合物2-3(603mg，2.41mmol，95%)。 Was added to the compound of 2-2 (896mg, 2.54mmol) in MeOH (12ml) in a solution of H 2 O (6.34ml, 12.7mmol) 4mol / L HCl at room temperature. After stirring at the same temperature for 1 h, the reaction mixture was treated with aqueous NaHCO 3 and aqueous layer was extracted with EtOAc. , 2 O and dried combined organic layers were washed with brine H over Na 2 SO 4, filtered and concentrated. The crude product was added to a silica gel column and was dissolved with hexanes/EtOAc 20%. The collected fractions were evaporated to give compound 2-3 (603 mg, 2.

1H-NMR(400MHz,CDCl3)δ：1.50(s,3H),3.17(d,J=17.8Hz,1H),3.53(d,J=17.8Hz,1H),5.06(s,1H),7.18(t,J=9.8Hz,1H),7.26-7.31(m,1H),7.63-7.56(m,1H),7.86(t,J=7.5Hz,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.50 (s, 3H), 3.17 (d, J = 17.8Hz, 1H), 3.53 (d, J = 17.8Hz, 1H), 5.06 (s, 1H), 7.18 (t, J = 9.8 Hz, 1H), 7.26 - 7.31 (m, 1H), 7.63 - 7.56 (m, 1H), 7.86 (t, J = 7.5 Hz, 1H).

步驟3 Step 3

向化合物2-3(500mg，2.00mmol)於甲苯(5ml)中之溶液中添加乙醇鈦(0.836ml，4.00mmol)及(S)-2-甲基丙烷-2-亞磺醯胺(363mg， 3.00mmol)。在80℃下攪拌15分鐘之後，在室溫下向反應混合物添加MeCN(10ml)及H2O(0.25mL)，且藉由過濾移除不溶材料。在減壓下蒸發濾液。將粗產物添加至矽膠管柱且用己烷/EtOAc 30%溶離。蒸發收集之溶離份，獲得呈白色固體狀之化合物2-4(588mg，1.66mmol，83%)。 To a solution of the compound 2-3 (500 mg, 2.00 mmol) in toluene (5 ml), EtOAc (EtOAc, EtOAc, EtOAc, 3.00mmol). After stirring at 80 ° C for 15 minutes, MeCN (10 ml) and H 2 O (0.25 mL) were added to the reaction mixture at room temperature, and the insoluble material was removed by filtration. The filtrate was evaporated under reduced pressure. The crude product was added to a silica gel column and was eluted with hexanes/EtOAc 30%. The collected fractions were evaporated to give compound 2-4 (m.

1H-NMR(400MHz,CDCl3)δ：1.33(s,3H),1.37(s,9H),3.35(d,J=13.0Hz,1H),3.95(d,J=13.0Hz,1H),5.89(s,1H),7.07-7.25(m,2H),7.54-7.40(m,2H)。 1 H-NMR (400MHz, CDCl3 ) δ: 1.33 (s, 3H), 1.37 (s, 9H), 3.35 (d, J = 13.0Hz, 1H), 3.95 (d, J = 13.0Hz, 1H), 5.89 (s, 1H), 7.07-7.25 (m, 2H), 7.54-7.40 (m, 2H).

步驟4 Step 4

在室溫下向化合物2-4(550mg，1.56mmol)於DMF(5ml)中之溶液中添加咪唑(318mg，4.67mmol)、TMSCl(338mg，3.11mmol)及DMAP(95.0mg，0.778mmol)。在相同溫度下攪拌40分鐘之後，用H2O處理反應混合物。用AcOEt萃取水層，且經Na2SO4乾燥有機層，過濾且濃縮。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至20%溶離。蒸發收集之溶離份，獲得呈黃色油狀之化合物2-5(406mg，0.954mmol，61%)。 To a solution of compound 2-4 (550 mg, 1.56 mmol) in DMF (5 ml), EtOAc (EtOAc, EtOAc, EtOAc, EtOAc After stirring at the same temperature for 40 minutes, the reaction mixture was treated with H 2 O. The aqueous layer was extracted with AcOEt, and organic layer and dried over Na 2 SO 4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with hexanes/EtOAc from 0% to 20%. The collected fractions were evaporated to give compound 2-5 (406 mg, <RTIgt;

1H-NMR(400MHz,CDCl3)δ：-0.14(s,9H),1.30(s,9H),1.42(s,3H),3.61(d,J=13.2Hz,1H),3.99(d,J=13.2Hz,1H),7.07(dd,J=8.4,10.7Hz,1H),7.17(t,J=7.4Hz,1H),7.43-7.35(m,1H),7.46-7.53(m,1H)。 1 H-NMR (400MHz, CDCl 3) δ: -0.14 (s, 9H), 1.30 (s, 9H), 1.42 (s, 3H), 3.61 (d, J = 13.2Hz, 1H), 3.99 (d, J = 13.2 Hz, 1H), 7.07 (dd, J = 8.4, 10.7 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H), 7.43 - 7.35 (m, 1H), 7.46 - 7.53 (m, 1H) ).

步驟5 Step 5

在-78℃下向化合物2-5(200mg，0.470mmol)於THF(3ml)中之溶液中添加MeLi(***中之1.13mmol/L，1.25mL，1.41mmol)之溶液。在0℃下攪拌30分鐘之後，用NH4Cl水溶液處理反應混合物。用AcOEt萃取水層，且經Na2SO4乾燥有機層，過濾且濃縮。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至30%溶離。蒸發收集之溶離 份，獲得呈無色油狀之化合物2-6(18.0mg，0.0408mmol，8.7%)。 A solution of MeLi (1.13 mmol/L in diethyl ether, 1.25 mL, 1.41 mmol) was added to a solution of compound 2-5 (200 mg, 0.470 mmol) in THF (3 mL). After stirring at 0 ° C for 30 minutes, the reaction mixture was treated with aqueous NH 4 Cl. The aqueous layer was extracted with AcOEt, and organic layer and dried over Na 2 SO 4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with hexane / EtOAc from 0% to 30%. The collected fractions were evaporated to give compound 2-6 (18.0 mg, <RTIgt;

1H-NMR(400MHz,CDCl3)δ：0.01(s,9H),1.06(s,3H),1.28(s,9H),1.69(s,3H),2.30(d,J=15.1Hz,1H),2.53(d,J=15.1Hz,1H),5.54(s,1H),6.96-7.03(m,1H),7.24-7.17(m,2H),8.14(t,J=8.0Hz,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 0.01 (s, 9H), 1.06 (s, 3H), 1.28 (s, 9H), 1.69 (s, 3H), 2.30 (d, J = 15.1Hz, 1H ), 2.53 (d, J = 15.1 Hz, 1H), 5.54 (s, 1H), 6.96 - 7.03 (m, 1H), 7.24 - 7.17 (m, 2H), 8.14 (t, J = 8.0 Hz, 1H) .

步驟6 Step 6

在室溫下向化合物2-6(86.0mg，0.195mmol)於MeOH(1ml)中之溶液中添加二烷(0.292ml，1.17mmol)中之4mol/L HCl。在相同溫度下攪拌17h之後，用NaHCO3水溶液處理反應混合物，且用CHCl3萃取水層。合併之有機層經Na2SO4乾燥，過濾且濃縮，得到化合物2-7，其不經純化即用於下一步驟。 To the solution of compound 2-6 (86.0 mg, 0.195 mmol) in MeOH (1 mL) 4 mol/L HCl in alkane (0.292 ml, 1.17 mmol). After stirring at the same temperature for 17h, treated with aqueous NaHCO 3 solution the reaction mixture, and the aqueous layer was extracted with CHCl 3. The combined organic layer was dried over Na 2 SO 4, filtered and concentrated to give compound 2-7, which was used without purification in the next step.

在0℃下向2-7於CH2Cl2(1ml)中之溶液中添加異硫氰酸苯甲醯酯(0.0400ml，0.292mmol)。在室溫下攪拌2.5h之後，濃縮反應混合物。將所得殘餘物添加至矽膠管柱中且用己烷/EtOAc 0%至25%溶離。蒸發收集之溶離份，獲得呈黃色油狀之2-8(72.0mg，0.168mmol，86%)。 Was added benzoyl isothiocyanate (0.0400ml, 0.292mmol) in the solution at 0 ℃ to 2-7 in CH 2 Cl 2 (1ml). After stirring at room temperature for 2.5 h, the reaction mixture was concentrated. The residue obtained was added to a silica gel column and lysed with hexane / EtOAc from 0% to 25%. The collected fractions were evaporated to give 2-8 (yield: <RTIgt;

1H-NMR(400MHz,CDCl3)δ：1.31(s,3H),2.25(s,3H),2.66(d,J=15.2Hz,1H),2.98(d,J=15.2Hz,1H),7.02-7.09(m,1H),7.16(t,J=7.1Hz,1H),7.27-7.33(m,1H),7.45(t,J=7.7Hz,1H),7.52(t,J=7.7Hz,2H),7.63(t,J=7.7Hz,1H),7.86(d,J=7.7Hz,2H),8.83(s,1H),11.65(s,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.31 (s, 3H), 2.25 (s, 3H), 2.66 (d, J = 15.2Hz, 1H), 2.98 (d, J = 15.2Hz, 1H), 7.02-7.09(m,1H),7.16(t,J=7.1Hz,1H), 7.27-7.33(m,1H), 7.45(t,J=7.7Hz,1H),7.52(t,J=7.7Hz , 2H), 7.63 (t, J = 7.7 Hz, 1H), 7.86 (d, J = 7.7 Hz, 2H), 8.83 (s, 1H), 11.65 (s, 1H).

步驟7 Step 7

在室溫下向化合物2-8(72.0mg，0.168mmol)於MeCN(1ml)中之溶液中添加WSCD．HCl(64.4mg，0.336mmol)。在相同溫度下攪拌20小時後，濃縮反應混合物。將所得殘餘物添加至矽膠管柱中且用己烷/EtOAc 0%至20%溶離。蒸發收集之溶離份，獲得呈無色油狀之化合 物2-9(55.0mg，0.139mmol，83%)。 WSCD was added to a solution of compound 2-8 (72.0 mg, 0.168 mmol) in MeCN (1 mL) at room temperature. HCl (64.4 mg, 0.336 mmol). After stirring at the same temperature for 20 hours, the reaction mixture was concentrated. The resulting residue was added to a silica gel column and was eluted with hexane / EtOAc from 0% to 20%. Evaporating the collected fractions to obtain a colorless oily compound 2-9 (55.0 mg, 0.139 mmol, 83%).

1H-NMR(400MHz,CDCl3)δ：1.11(s,3H),1.82(s,3H),2.43(d,J=14.3Hz,1H),3.06(d,J=14.3Hz,1H),7.10-7.21(m,2H),7.32-7.47(m,4H),7.52(t,J=7.3Hz,1H),8.28(d,J=7.3Hz,2H),11.94(s,1H)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.11 (s, 3H), 1.82 (s, 3H), 2.43 (d, J = 14.3 Hz, 1H), 3.06 (d, J = 14.3 Hz, 1H), 7.10-7.21 (m, 2H), 7.32-7.47 (m, 4H), 7.52 (t, J = 7.3 Hz, 1H), 8.28 (d, J = 7.3 Hz, 2H), 11.94 (s, 1H).

步驟8 Step 8

在室溫下向化合物2-9(55.0mg，0.139mmol)於MeOH(1ml)中之溶液中添加K2CO3(57.8mg，0.418mmol)。在50℃下攪拌4h之後，用H2O處理反應混合物，且用AcOEt萃取水層。合併之有機層經Na2SO4乾燥，過濾且濃縮，得到化合物2-10，其不經純化即用於下一步驟。 K is added to the medium (55.0mg, 0.139mmol) in MeOH (1ml) solution of the compound 2-9 at room temperature for 2 CO 3 (57.8mg, 0.418mmol) . After stirring at 50 ° C for 4 h, the reaction mixture was treated with H 2 O and aqueous layer was extracted with AcOEt. The combined organic layer was dried over Na 2 SO 4, filtered and concentrated to give compound 2-10, which was used without purification in the next step.

在-20℃下向2-10於TFA(1ml)中之溶液中添加硫酸(0.245ml，4.60mmol)。在0℃下攪拌5分鐘之後，將反應混合物在-20℃下添加至HNO3(0.00935ml，0.209mmol)中。在0℃下攪拌15分鐘之後，用K2CO3水溶液處理反應混合物。用AcOEt萃取水層且經Na2SO4乾燥有機層。於真空中濃縮濾液，得到呈黃色油狀之化合物2-11，其不經純化即用於下一步驟。 Sulfuric acid (0.245 ml, 4.60 mmol) was added to a solution of 2-10 in TFA (1 mL). After stirring at 0 ℃ 5 minutes, the reaction mixture was added to HNO 3 (0.00935ml, 0.209mmol) at -20 ℃. After stirring at 0 ° C for 15 minutes, the reaction mixture was treated with aqueous K 2 CO 3 . The aqueous layer was extracted with EtOAc and dried over Na 2 SO 4 . The filtrate was concentrated in vacuo to afford compound 2-11 as a yellow oil.

在室溫下向2-11於THF(1ml)中之溶液中添加Boc2O(0.0970ml，0.419mmol)及DMAP(6.82mg，0.0560mmol)。在相同溫度下攪拌1h之後，在真空下濃縮混合物。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至20%溶離。蒸發收集之溶離份，獲得呈白色固體狀之化合物2-12(70.0mg，0.131mmol，94%)。 Boc 2 O (0.0970 ml, 0.419 mmol) and DMAP (6.82 mg, 0.0560 mmol) were added to a solution of 2-11 in THF (1 mL). After stirring at the same temperature for 1 h, the mixture was concentrated under vacuum. The crude product was added to a silica gel column and was eluted with hexanes/EtOAc from 0% to 20%. The collected fractions were evaporated to give compound 2-2 (70.0 mg, 0.131 mmol, 94%) as a white solid.

1H-NMR(400MHz,CDCl3)δ：1.09(s,3H),1.53(s,18H),1.66(s,3H),2.19(d,J=14.8Hz,1H),2.90(d,J=14.8Hz,1H),7.28-7.24(m,1H),8.19-8.24(m,1H),8.59(dd,J=6.9,2.9Hz,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.09 (s, 3H), 1.53 (s, 18H), 1.66 (s, 3H), 2.19 (d, J = 14.8Hz, 1H), 2.90 (d, J =14.8 Hz, 1H), 7.28-7.24 (m, 1H), 8.19-8.24 (m, 1H), 8.59 (dd, J = 6.9, 2.9 Hz, 1H).

步驟9 Step 9

在氫氣氛圍下在室溫下攪拌2-12(70.0mg，0.131mmol)及10% Pd/C(7.05mg)於MeOH(3ml)中之懸浮液。在相同溫度下攪拌1.5h之後，經由矽藻土(註冊商標)墊過濾混合物。於真空中濃縮濾液，得到呈白色固體狀之化合物2-13(57.0mg，0.113mmol，86%)，其不經純化即用於下一步驟。 A suspension of 2-12 (70.0 mg, 0.131 mmol) and 10% Pd/C (7.05 mg) in MeOH (3 mL) was stirred at room temperature. After stirring at the same temperature for 1.5 h, the mixture was filtered through a pad of diatomaceous earth (registered trademark). The filtrate was concentrated in vacuo tolulululululululululululululu

1H-NMR(400MHz,CDCl3)δ：1.14(s,3H),1.52(s,18H),1.61(s,3H),2.04(d,J=14.2Hz,1H),2.93(d,J=14.2Hz,1H),3.51(s,2H),6.55-6.50(m,1H),6.89-6.81(m,2H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.14 (s, 3H), 1.52 (s, 18H), 1.61 (s, 3H), 2.04 (d, J = 14.2Hz, 1H), 2.93 (d, J =14.2 Hz, 1H), 3.51 (s, 2H), 6.55-6.50 (m, 1H), 6.89-6.81 (m, 2H).

步驟10 Step 10

在室溫下向2-13(57.0mg，0.113mmol)於DMF(1ml)中之溶液中添加5-氰基吡啶甲酸水合物(18.7mg，0.113mmol)、HATU(51.4mg，0.135mmol)及DIPEA(0.0390ml，0.226mmol)。在相同溫度下攪拌1h之後，用H2O處理反應混合物。用AcOEt萃取水層，且經Na2SO4乾燥有機層，過濾且濃縮。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至30%溶離。蒸發收集之溶離份，獲得呈白色非晶形形式之化合物2-14(70.0mg，0.110mmol，98%)。 Add 5-cyanopicolinic acid hydrate (18.7 mg, 0.113 mmol), HATU (51.4 mg, 0.135 mmol) to a solution of 2-13 (57.0 mg, 0.113 mmol) in DMF (1 mL). DIPEA (0.0390 ml, 0.226 mmol). After stirring at the same temperature for 1 h, the reaction mixture was treated with H 2 O. The aqueous layer was extracted with AcOEt, and organic layer and dried over Na 2 SO 4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with hexane / EtOAc from 0% to 30%. The collected fractions were evaporated to give compound 2-14 (70.0 mg, 0.110 mmol, 98%).

1H-NMR(400MHz,CDCl3)δ：1.11(s,3H),1.54(s,18H),1.67(s,3H),2.12(d,J=14.3Hz,1H),2.94(d,J=14.3Hz,1H),7.13(dd,J=11.5,9.0Hz,1H),7.53(dd,J=7.0,2.6Hz,1H),8.21(dd,J=8.2,1.8Hz,1H),8.32-8.27(m,1H),8.43(d,J=8.2Hz,1H),8.80(s,1H),9.91(s,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.11 (s, 3H), 1.54 (s, 18H), 1.67 (s, 3H), 2.12 (d, J = 14.3Hz, 1H), 2.94 (d, J =14.3 Hz, 1H), 7.13 (dd, J=11.5, 9.0 Hz, 1H), 7.53 (dd, J=7.0, 2.6 Hz, 1H), 8.21 (dd, J=8.2, 1.8 Hz, 1H), 8.32 - 8.27 (m, 1H), 8.43 (d, J = 8.2 Hz, 1H), 8.80 (s, 1H), 9.91 (s, 1H).

步驟11 Step 11

在室溫下攪拌化合物2-14(70.0mg，0.110mmol)於甲酸(0.972ml)中之溶液19h。用K2CO3水溶液處理反應混合物。用AcOEt萃取水層，且經Na2SO4乾燥有機層，過濾且濃縮，獲得呈白色固體狀之化合物I-7(40.0mg，0.0920mmol，83%)。 A solution of compound 2-14 (70.0 mg, 0.110 mmol) in EtOAc. The reaction mixture was treated with aq. K 2 CO 3 . The aqueous layer was extracted with AcOEt, and organic layer and dried over Na 2 SO 4, filtered and concentrated to give a white solid of Compound I-7 (40.0mg, 0.0920mmol, 83%).

實例3 合成化合物I-8 Example 3 Synthesis of Compound I-8

步驟1 step 1

在室溫下向化合物3-1(373mg，1.24mmol)於MeOH(4ml)中之溶液中添加二烷(0.464ml，1.86mmol)中之4mol/L HCl。在相同溫度下攪拌30分鐘之後，用NaHCO3水溶液處理反應混合物且用AcOEt萃取水層。用H2O及鹽水洗滌經合併之有機層，經Na2SO4乾燥且過濾。於真空中濃縮濾液，得到呈褐色油狀之化合物3-2，其不經純化即用於下一步驟。 To the solution of compound 3-1 (373 mg, 1.24 mmol) in MeOH (4 mL) 4 mol/L HCl in alkane (0.464 ml, 1.86 mmol). After stirring at the same temperature for 30 minutes, the reaction mixture was treated with aqueous NaHCO 3 and the aqueous layer was extracted with AcOEt. H 2 O was washed with brine and the organic layers were combined, dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to afford compound 3-2 as a brown oil.

在0℃下向化合物3-2於CH2Cl2(3ml)中之溶液中添加異硫氰酸苯甲醯酯(0.255ml，1.86mmol)。在室溫下攪拌30分鐘之後，濃縮反應 混合物。將所得殘餘物添加至矽膠管柱中且用己烷/EtOAc 0%至25%溶離。蒸發收集之溶離份，獲得呈白色非晶形形式之化合物3-3(397mg，1.10mmol，89%)。 At 3-2 to a solution of compound 0 ℃ CH 2 Cl 2 (3ml ) was added in the benzoyl isothiocyanate (0.255ml, 1.86mmol). After stirring at room temperature for 30 minutes, the reaction mixture was concentrated. The residue obtained was added to a silica gel column and lysed with hexane / EtOAc from 0% to 25%. The collected fractions were evaporated to give compound 3-3 (397 mg, 1.10 mmol, 89%).

1H-NMR(400MHz,CDCl3)δ：2.13(s,3H),5.48(d,J=10.6Hz,1H),5.60-5.76(m,2H),5.82-5.96(m,1H),7.00-7.07(m,1H),7.16(t,J=7.7Hz,1H),7.27-7.33(m,1H),7.44(t,J=7.7Hz,1H),7.51(t,J=7.7Hz,2H),7.63(t,J=7.7Hz,1H),7.85(d,J=7.7Hz,2H),8.82(s,1H),11.50(s,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 2.13 (s, 3H), 5.48 (d, J = 10.6Hz, 1H), 5.60-5.76 (m, 2H), 5.82-5.96 (m, 1H), 7.00 -7.07 (m, 1H), 7.16 (t, J = 7.7 Hz, 1H), 7.27-7.33 (m, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 7.63 (t, J = 7.7 Hz, 1H), 7.85 (d, J = 7.7 Hz, 2H), 8.82 (s, 1H), 11.50 (s, 1H).

步驟2 Step 2

在0℃下向碘(559mg，2.20mmol)於MeCN(30ml)中之溶液中添加MeCN(10ml)中之化合物3-3(397mg，1.10mmol)。在相同溫度下攪拌20分鐘之後，用NaHCO3及Na2S2O3水溶液處理反應混合物。用AcOEt萃取水層。用鹽水洗滌合併之有機層，經Na2SO4乾燥，過濾且濃縮。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至20%溶離。蒸發收集之溶離份，獲得呈白色非晶形形式之化合物3-4(489mg，1.01mmol，91%)。 To a solution of iodine (559 mg, 2.20 mmol) in MeCN (30 mL), Compound 3-3 (397 mg, 1. After stirring at the same temperature for 20 minutes, the reaction mixture was treated with aqueous NaHCO 3 and Na 2 S 2 O 3 . The aqueous layer was extracted with AcOEt. , Dried combined organic layers were washed with brine, Na 2 SO 4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with hexanes/EtOAc from 0% to 20%. The collected fractions were evaporated to give compound 3-4 (yield: </RTI><RTIgt;

1H-NMR(400MHz,CDCl3)δ：1.90(s,3H),3.14-3.28(m,2H),3.50(t,J=9.3Hz,1H),5.70(d,J=47.3Hz,1H),7.12-7.23(m,2H),7.31-7.48(m,4H),7.53(t,J=7.3Hz,1H),8.21(d,J=7.3Hz,2H)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.90 (s, 3H), 3.14 - 3.28 (m, 2H), 3.50 (t, J = 9.3 Hz, 1H), 5.70 (d, J = 47.3 Hz, 1H) ), 7.12 - 7.23 (m, 2H), 7.31 - 7.48 (m, 4H), 7.53 (t, J = 7.3 Hz, 1H), 8.21 (d, J = 7.3 Hz, 2H).

步驟3 Step 3

在室溫下向化合物3-4(489mg，1.01mmol)於甲苯(5ml)中之溶液中添加Bu3SnH(0.320ml，1.21mmol)及AIBN(8.26mg，0.0500mmol)。在80℃下攪拌100分鐘之後，濃縮反應混合物。將所得殘餘物添加至胺基矽膠管柱中且用己烷/EtOAc 0%至20%溶離。蒸發收集之溶離份，獲得呈白色非晶形形式之化合物3-5(336mg，0.932mmol，93%)。 Add a solution of compound 3-4 (489mg, 1.01mmol) in toluene (5ml) in a solution of Bu 3 SnH (0.320ml, 1.21mmol) and AIBN (8.26mg, 0.0500mmol). After stirring at 80 ° C for 100 minutes, the reaction mixture was concentrated. The residue obtained was added to an amine oxime column and lysed with hexane / EtOAc from 0% to 20%. The collected fractions were evaporated to give compound 3-5 (336 mg, 0.932 mmol, 93%) as white white.

1H-NMR(400MHz,CDCl3)δ：1.40(d,J=6.7Hz,3H),1.88(s,3H),3.13(dq,J=31.4,6.7Hz,1H),5.25(d,J=47.2Hz,1H),7.11(dd,J=12.3,8.0Hz,1H),7.20(t,J=7.5Hz,1H),7.33-7.46(m,4H),7.51(t,J=7.5Hz,1H),8.22(d,J=7.5Hz,2H),12.13(br s,1H)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.40 (d, J = 6.7 Hz, 3H), 1.88 (s, 3H), 3.13 (dq, J = 31.4, 6.7 Hz, 1H), 5.25 (d, J) =47.2 Hz, 1H), 7.11 (dd, J = 12.3, 8.0 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.33 - 7.46 (m, 4H), 7.51 (t, J = 7.5 Hz) , 1H), 8.22 (d, J = 7.5 Hz, 2H), 12.13 (br s, 1H).

步驟4 Step 4

在室溫下向化合物3-5(336mg，0.932mmol)於EtOH(3ml)中之溶液中添加水合肼(0.226ml，4.66mmol)。在相同溫度下攪拌14小時後，濃縮反應混合物。將所得殘餘物添加至胺基矽膠管柱中且用己烷/EtOAc 10%至50%溶離。蒸發收集之溶離份，獲得呈白色固體狀之化合物3-6(195mg，0.761mmol，82%)。 Hydrazine hydrate (0.226 ml, 4.66 mmol) was added to a solution of compound 3-5 (336 mg, 0.932 mmol) in EtOH (3 ml). After stirring at the same temperature for 14 hours, the reaction mixture was concentrated. The resulting residue was added to an amine oxime column and lysed with hexanes/EtOAc 10% to 50%. The collected fractions were evaporated to give compound 3-6 (195 mg,j.

1H-NMR(400MHz,CDCl3)δ：1.32(d,J=6.8Hz,3H),3.08-2.94(m,1H),5.09(d,J=47.4Hz,1H),6.99-7.07(m,1H),7.12(t,J=7.4Hz,1H),7.23-7.31(m,2H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.32 (d, J = 6.8Hz, 3H), 3.08-2.94 (m, 1H), 5.09 (d, J = 47.4Hz, 1H), 6.99-7.07 (m , 1H), 7.12 (t, J = 7.4 Hz, 1H), 7.23 - 7.31 (m, 2H).

步驟5 Step 5

在-20℃下向化合物3-6於TFA(2ml)中之溶液中添加硫酸(0.507ml，9.51mmol)。在0℃下攪拌5分鐘之後，將反應混合物在-20℃下添加至HNO3(0.0510ml，1.14mmol)中。在0℃下攪拌20分鐘之後，用K2CO3水溶液處理反應混合物。用AcOEt萃取水層且經Na2SO4乾燥有機層。於真空中濃縮濾液，得到呈黃色油狀之化合物3-7，其不經純化即用於下一步驟。 Sulfuric acid (0.507 ml, 9.51 mmol) was added to a solution of compound 3-6 in EtOAc (2 mL). After stirring at 0 ℃ 5 minutes, the reaction mixture was added to HNO 3 (0.0510ml, 1.14mmol) at -20 ℃. After stirring at 0 ° C for 20 minutes, the reaction mixture was treated with aqueous K 2 CO 3 . The aqueous layer was extracted with EtOAc and dried over Na 2 SO 4 . The filtrate was concentrated in vacuo to afford compound 3-7 as a yellow oil.

在室溫下向化合物3-7於THF(2ml)中之溶液中添加Boc2O(0.529ml，2.28mmol)及DMAP(37.1mg，0.304mmol)。在相同溫度下攪拌50分鐘之後，在真空下濃縮混合物。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至40%溶離。蒸發收集之溶離份，獲得呈白色非晶形形式之化合物3-8(381mg，0.760mmol，定量)。 Add Boc 2 O (0.529ml, 2.28mmol) and DMAP (37.1mg, 0.304mmol) of the compound 3-7 in THF (2ml) solution at room temperature. After stirring at the same temperature for 50 minutes, the mixture was concentrated under vacuum. The crude product was added to a silica gel column and was eluted with hexanes/EtOAc from 0% to 40%. The collected fractions were evaporated to give compound 3-8 (381 mg, 0.760 mmol, quantitative) in white amorphous form.

1H-NMR(400MHz,CDCl3)δ：1.37(d,J=6.8Hz,3H),1.55(s, 18H),1.82(s,3H),3.09(dq,J=29.6,6.8Hz,1H),5.12(d,J=46.7Hz,1H),7.23(dd,J=10.9,9.1Hz,1H),8.23-8.18(m,1H),8.52(dd,J=6.6,2.8Hz,1H)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.37 (d, J = 6.8 Hz, 3H), 1.55 (s, 18H), 1.82 (s, 3H), 3.09 (dq, J = 29.6, 6.8 Hz, 1H) ), 5.12 (d, J = 46.7 Hz, 1H), 7.23 (dd, J = 10.9, 9.1 Hz, 1H), 8.23-8.18 (m, 1H), 8.52 (dd, J = 6.6, 2.8 Hz, 1H) .

步驟6 Step 6

在室溫下向化合物3-8(381mg，0.760mmol)於EtOH(4ml)、THF(2ml)及H2O(2ml)中之溶液中添加NH4Cl(488mg，9.12mmol)及鐵粉(339mg，6.08mmol)。在60℃下攪拌90分鐘之後，用H2O處理混合物且經由矽藻土(註冊商標)墊過濾。用AcOEt萃取水層，且經Na2SO4乾燥有機層，過濾且濃縮。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至40%溶離。蒸發收集之溶離份，獲得呈白色非晶形形式之化合物3-9(247mg，0.524mmol，69%)。 To a solution of compound 3-8 (381mg, 0.760mmol) in EtOH (4ml), the in THF (2ml) and H 2 O (2ml) was added NH 4 Cl (488mg, 9.12mmol) and iron powder ( 339 mg, 6.08 mmol). After stirring at 60 ° C for 90 minutes, the mixture was treated with H 2 O and filtered through a pad of Celite (registered trademark). The aqueous layer was extracted with AcOEt, and organic layer and dried over Na 2 SO 4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with hexanes/EtOAc from 0% to 40%. The collected fractions were evaporated to give compound 3-9 (247 mg, 0.524 mmol, 69%).

1H-NMR(400MHz,CDCl3)δ：1.33(d,J=7.0Hz,3H),1.54(s,18H),1.80(t,J=2.0Hz,3H),3.19(dq,J=29.6,7.0Hz,1H),3.57(s,2H),5.05(d,J=48.2Hz,1H),6.55-6.51(m,1H),6.88-6.80(m,2H)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.33 (d, J = 7.0 Hz, 3H), 1.54 (s, 18H), 1.80 (t, J = 2.0 Hz, 3H), 3.19 (dq, J = 29.6) , 7.0 Hz, 1H), 3.57 (s, 2H), 5.05 (d, J = 48.2 Hz, 1H), 6.55-6.51 (m, 1H), 6.88-6.80 (m, 2H).

步驟7 Step 7

在室溫下向化合物3-9(60.0mg，0.127mmol)於DMF(1ml)中之溶液中添加5-甲氧基吡-2-甲酸(20.6mg，0.134mmol)、HATU(58.1mg，0.153mmol)及DIPEA(0.0440ml，0.254mmol)。在相同溫度下攪拌20分鐘之後，用H2O處理反應混合物。用AcOEt萃取水層，且經Na2SO4乾燥有機層，過濾且濃縮。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至30%溶離。蒸發收集之溶離份，獲得呈白色固體狀之化合物3-10(70.0mg，0.115mmol，91%)。 Add 5-methoxypyridyl to a solution of compound 3-9 (60.0 mg, 0.127 mmol) in DMF (1 mL) 2-carboxylic acid (20.6 mg, 0.134 mmol), HATU (58.1 mg, 0.153 mmol) and DIPEA (0.0440 ml, 0.254 mmol). After stirring at the same temperature for 20 minutes, the reaction mixture was treated with H 2 O. The aqueous layer was extracted with AcOEt, and organic layer and dried over Na 2 SO 4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with hexane / EtOAc from 0% to 30%. The collected fractions were evaporated to give compound 3-10 (70.0 mg, 0.115 mmol, 91%).

1H-NMR(400MHz,CDCl3)δ：1.35(d,J=7.0Hz,3H),1.58(s,18H),1.86(s,3H),3.17(dq,J=30.5,7.0Hz,1H),4.06(s,3H),5.09(d,J=46.8Hz,1H),7.10(dd,J=9.3,11.7Hz,1H),7.51(d,J=6.7Hz,1H),8.06(s,1H),8.44-8.39(m,1H),9.01(s,1H),9.69(s,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.35 (d, J = 7.0Hz, 3H), 1.58 (s, 18H), 1.86 (s, 3H), 3.17 (dq, J = 30.5,7.0Hz, 1H ), 4.06 (s, 3H), 5.09 (d, J = 46.8 Hz, 1H), 7.10 (dd, J = 9.3, 11.7 Hz, 1H), 7.51 (d, J = 6.7 Hz, 1H), 8.06 (s) , 1H), 8.44 - 8.39 (m, 1H), 9.01 (s, 1H), 9.69 (s, 1H).

步驟8 Step 8

在室溫下攪拌化合物3-10(70.0mg，0.115mmol)於甲酸(0.972ml)中之溶液19h。用K2CO3水溶液處理反應混合物。用AcOEt萃取水層，且經Na2SO4乾燥有機層，過濾且濃縮，獲得呈白色固體狀之化合物I-8(35.0mg，0.0860mmol，75%)。 A solution of compound 3-10 (70.0 mg, 0.115 mmol) in EtOAc. The reaction mixture was treated with aq. K 2 CO 3 . The aqueous layer was extracted with AcOEt, and organic layer and dried over Na 2 SO 4, filtered and concentrated to afford the form (35.0mg, 0.0860mmol, 75%) as a white solid of the Compound I-8.

實例4 合成化合物I-13 Example 4 Synthesis of Compound I-13

步驟1 step 1

向化合物4-1(15.0g，43.2mmol)於甲醇(150ml)中之溶液中添加HCl-二烷(4M，15.1ml，60.4mmol)。在室溫下攪拌1h之後，用NaHCO3飽和水溶液淬滅反應混合物。用AcOEt萃取水相。經Na2SO4 乾燥有機層且濃縮，獲得化合物4-2(10.5g，定量)，其不經進一步純化即用於下一反應。 Add HCl-II to a solution of compound 4-1 (15.0 g, 43.2 mmol) in methanol (150 ml) Alkane (4M, 15.1 ml, 60.4 mmol). After stirring at room temperature for 1h, washed with saturated aqueous NaHCO 3 to quench the reaction mixture. The aqueous phase was extracted with AcOEt. Dried over Na 2 SO 4, and the organic layer was concentrated to obtain compound 4-2 (10.5g, quantitative), which was used without further purification in the next reaction.

LC/MS(Shimadzu)：RT 0.83,MS計算值244.10(M+H+)，實驗值244.30。 </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI>

步驟2 Step 2

在0℃下向化合物4-2(10.5g，43.2mmol)及NaHCO3(12.7g，151mmol)於AcOEt(100ml)及H2O(50ml)中之溶液中添加氯甲酸4-硝基苯酯(8.71g，43.2mmol)。在0℃下攪拌1h之後，添加雙(2,4-二甲氧基苯甲基)胺(13.7g，43.2mmol)。在0℃下再攪拌1h之後，用H2O淬滅反應混合物，且用AcOEt萃取水相。用K2CO3水溶液及H2O洗滌有機相兩次以移除4-硝基苯酚。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物4-3(25.3g，43.1mmol，100%，包括少量4-硝基苯酚)。 At 0 ℃ solution of compound 4-2 (10.5g, 43.2mmol) and NaHCO 3 (12.7g, 151mmol) in AcOEt was added 4-nitrophenyl ester of (100ml) and H 2 O (50ml) solution of (8.71 g, 43.2 mmol). After stirring at 0 ° C for 1 h, bis(2,4-dimethoxybenzyl)amine (13.7 g, 43.2 mmol) was added. After stirring at 0 ℃ 1h, quenched with H 2 O the reaction mixture, and the aqueous phase was extracted with AcOEt. The organic phase was washed twice with aqueous K 2 CO 3 and H 2 O to remove 4-nitrophenol. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to afford compound 4-3 (25.3 g, 43.1 mmol, 100%, including a small amount of 4-nitrophenol).

1H-NMR(CDCl3)δ：0.97(t,J=7.2Hz,3H),1.95(s,3H),3.80(s,6H),3.81(s,6H),3.87(dq,J=10.6,7.2Hz,1H),4.01(dq,J=10.6,7.2Hz,1H),4.33(d,J=16.2Hz,2H),4.42(d,J=16.2Hz,2H),5.58(d,J=47.8Hz,1H),6.07(s,1H),6.42-6.49(m,4H),7.00(m,1H),7.08(m,1H),7.18(d,J=8.8Hz,2H),7.24(m,1H),7.36(m,1H)。 1 H-NMR (CDCl 3 ) δ: 0.97 (t, J = 7.2 Hz, 3H), 1.95 (s, 3H), 3.80 (s, 6H), 3.81 (s, 6H), 3.87 (dq, J = 10.6) , 7.2 Hz, 1H), 4.01 (dq, J = 10.6, 7.2 Hz, 1H), 4.33 (d, J = 16.2 Hz, 2H), 4.42 (d, J = 16.2 Hz, 2H), 5.58 (d, J =47.8 Hz, 1H), 6.07 (s, 1H), 6.42-6.49 (m, 4H), 7.00 (m, 1H), 7.08 (m, 1H), 7.18 (d, J = 8.8 Hz, 2H), 7.24 (m, 1H), 7.36 (m, 1H).

步驟3 Step 3

在-65℃下向化合物4-3(25.3g，43.2mmol，包括少量4-硝基苯酚)於CH2Cl2(125ml)中之溶液中添加DIBAL(甲苯中之1.02mol/L，127ml，130mmol)。在-65℃下攪拌1h之後，用H2O中之AcOEt及羅謝爾鹽(98g，346mmol)淬滅反應混合物。在室溫下再攪拌2h之後，用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物4-4(19.5g，35.9mmol，3個步驟中之83%)。 Add DIBAL (1.02 mol/L in toluene, 127 ml) to a solution of compound 4-3 (25.3 g, 43.2 mmol, including a small amount of 4-nitrophenol) in CH 2 Cl 2 (125 mL). 130mmol). After stirring at -65 ℃ 1h, with H 2 O and AcOEt are of Rochelle salt (98g, 346mmol) The reaction mixture was quenched. After stirring at room temperature for additional 2 h, the aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to afford compound 4-4 (19.5 g, 35.9 mmol, 83% of 3 steps).

1H-NMR(CDCl3)δ：1.67(s,3H),3.80(s,6H),3.81(s,6H),4.36 (d,J=15.9Hz,2H),4.43(d,J=15.9Hz,2H),5.76(d,J=46.9Hz,1H),5.77(s,1H),6.43-6.51(m,4H),7.00-7.20(m,4H),7.22-7.35(m,2H),9.51(d,J=10.0Hz,1H)。 1 H-NMR (CDCl 3 ) δ: 1.67 (s, 3H), 3.80 (s, 6H), 3.81 (s, 6H), 4.36 (d, J = 15.9 Hz, 2H), 4.43 (d, J = 15.9) Hz, 2H), 5.76 (d, J = 46.9 Hz, 1H), 5.77 (s, 1H), 6.43 - 6.51 (m, 4H), 7.00-7.20 (m, 4H), 7.22 - 7.35 (m, 2H) , 9.51 (d, J = 10.0 Hz, 1H).

步驟4 Step 4

在0℃下向溴化乙基三苯基鏻(28.2g，76.0mmol)於THF(129ml)中之溶液中添加KHMDS(甲苯中之0.5mol/L，143ml，71.3mmol)。在逐滴KHMDS之後，將THF(80ml)中之化合物4-4(12.9g，23.8mmol)快速添加至反應混合物中。在0℃下攪拌30分鐘之後，將溫度升溫至50℃。在再攪拌1h之後，將反應混合物冷卻至0℃且用H2O淬滅。用AcOEt萃取水相，且經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得混合物形式之化合物4-5及4-6(12.4g，22.4mmol，94%，化合物4-5：化合物4-6=1.5：1)。 KHMDS (0.5 mol/L in toluene, 143 ml, 71.3 mmol) was added to a solution of ethyltriphenylphosphonium bromide (28.2 g, 76.0 mmol) in THF (129 ml). After the dropwise addition of KHMDS, compound 4-4 (12.9 g, 23.8 mmol) from THF (80 mL) was quickly added to the reaction mixture. After stirring at 0 ° C for 30 minutes, the temperature was raised to 50 ° C. After stirring for an additional 1 h, the reaction mixture was cooled to 0 ° C and was quenched with H 2 O. The aqueous phase was extracted with AcOEt, and the combined organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to give compound 4-5 and 4-6 (12.4 g, 22.4 mmol, 94%, Compound 4-5: Compound 4-6 = 1.5:1).

化合物4-5：1H-NMR(CDCl3)δ：1.54(m,3H),1.87(s,3H),3.78(s,6H),3.81(s,6H),4.31-4.47(m,4H),5.31(m,1H),5.58-5.83(m,3H),6.42-6.48(m,4H),6.97(m,1H),7.07(m,1H),7.10-7.17(m,2H),7.19(m,1H),7.37(m,1H)。 Compound 4-5: 1 H-NMR (CDCl 3 ) δ: 1.54 (m, 3H), 1.87 (s, 3H), 3.78 (s, 6H), 3.81 (s, 6H), 4.31-4.47 (m, 4H) ), 5.31 (m, 1H), 5.58-5.83 (m, 3H), 6.42-6.48 (m, 4H), 6.97 (m, 1H), 7.07 (m, 1H), 7.10-7.17 (m, 2H), 7.19 (m, 1H), 7.37 (m, 1H).

化合物4-6：1H-NMR(CDCl3)δ：1.57(m,3H),1.82(s,3H),3.78(s,6H),3.81(s,6H),4.37(m,4H),5.30(m,1H),5.45(dd,J=47.3,6.8Hz,1H),5.60(s,1H),5.71(m,1H),6.40-6.49(m,4H),6.98(dd,J=12.5,8.2Hz,1H),7.08(m,1H),7.13(d,J=8.5Hz,2H),7.21(m,1H),7.38(dd,J=8.2,8.0Hz,1H)。 Compound 4-6: 1 H-NMR (CDCl 3 ) δ: 1.57 (m, 3H), 1.82 (s, 3H), 3.78 (s, 6H), 3.81 (s, 6H), 4.37 (m, 4H), 5.30 (m, 1H), 5.45 (dd, J = 47.3, 6.8 Hz, 1H), 5.60 (s, 1H), 5.71 (m, 1H), 6.40-6.49 (m, 4H), 6.98 (dd, J = 12.5, 8.2 Hz, 1H), 7.08 (m, 1H), 7.13 (d, J = 8.5 Hz, 2H), 7.21 (m, 1H), 7.38 (dd, J = 8.2, 8.0 Hz, 1H).

步驟5 Step 5

在0℃下向碘(11.4g，44.7mmol)於乙腈(500ml)中之溶液中添加乙腈(125ml)中之化合物4-5及4-6(12.4g，22.4mmol)。在0℃下攪拌 1.5h之後，用Na2S2O3水溶液及NaHCO3飽和水溶液淬滅反應混合物。在真空中移除乙腈之後，用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物4-7(8.81g，13.0mmol，58%)及回收之化合物4-6(3.17g，5.72mmol，26%)。 To a solution of iodine (11.4 g, 44.7 mmol) in acetonitrile (500 mL) was added EtOAc (EtOAc) After stirring at 0 ℃ 1.5h, the reaction mixture was washed with Na 2 S 2 O 3 solution and quenched with saturated aqueous NaHCO 3. After removing the acetonitrile in vacuo, the aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to afford compound 4-7 (8.81 g, 13.0 mmol, 58%) and compound 4-6 (3.17 g, 5.72 mmol, 26%).

1H-NMR(CDCl3)δ：1.63(s,3H),1.84(d,J=7.0Hz,3H),3.63(dd,J=28.6,9.2Hz,1H),3.75(s,6H),3.82(s,6H),4.12(m,1H),4.49(d,J=15.9Hz,2H),4.65(d,J=15.9Hz,2H),5.37(d,J=48.8Hz,1H),6.41-6.50(m,4H),7.00(dd,J=11.9,8.3Hz,1H),7.06(dd,J=7.4,7.4Hz,1H),7.16-7.28(m,3H),7.42(dd,J=8.3,7.4Hz,1H)。 1 H-NMR (CDCl 3 ) δ: 1.63 (s, 3H), 1.84 (d, J = 7.0 Hz, 3H), 3.63 (dd, J = 28.6, 9.2 Hz, 1H), 3.75 (s, 6H), 3.82 (s, 6H), 4.12 (m, 1H), 4.49 (d, J = 15.9 Hz, 2H), 4.65 (d, J = 15.9 Hz, 2H), 5.37 (d, J = 48.8 Hz, 1H), 6.41-6.50 (m, 4H), 7.00 (dd, J = 11.9, 8.3 Hz, 1H), 7.06 (dd, J = 7.4, 7.4 Hz, 1H), 7.16-7.28 (m, 3H), 7.42 (dd, J = 8.3, 7.4 Hz, 1H).

步驟6 Step 6

在室溫下向18-crown-6(5.45g，20.6mmol)及KO2(1.47g，20.6mmol)於DMSO(40ml)中之溶液中添加DMSO(25ml)中之化合物4-7(3.51g，5.16mmol)。在攪拌25分鐘之後，用Na2S2O3飽和水溶液淬滅反應混合物。用AcOEt萃取水相，且經Na2SO4乾燥有機層。重複此反應3次(300mg、2.0g及3.0g 4-7用於各步驟中)。濃縮在各步驟中獲得之合併之有機層，且藉由矽膠層析純化殘餘物，獲得化合物4-8(2.05g，3.59mmol，28%，7.6：1非對映混合物，於C7位置處)。 To a solution of 18-crown-6 (5.45 g, 20.6 mmol) and KO 2 (1.47 g, 20.6 mmol) in DMSO (40 mL), EtOAc (25 mL) , 5.16mmol). After stirring for 25 minutes, washed with saturated aqueous Na 2 S 2 O 3 reaction mixture was quenched. And the organic layer was dried over Na 2 SO 4 aqueous phase was extracted with AcOEt,. This reaction was repeated 3 times (300 mg, 2.0 g, and 3.0 g of 4-7 for each step). The combined organic layers obtained in each step were concentrated, and the residue was purified by silica gel chromatography to afford compound 4-8 (2.05 g, 3.59 mmol, 28%, 7.6:1 diastereomeric mixture at C7 position) .

1H-NMR(CDCl3)δ：1.07(d,J=6.3Hz,3H),1.66(s,3H),3.35(dd,J=30.4,7.8Hz,1H),3.75(s,6H),3.81(s,6H),3.85(m,1H),4.45(d,J=15.9Hz,2H),4.61(d,J=15.9Hz,2H),5.38(d,J=48.6Hz,1H),6.41-6.50(m,4H),6.98(dd,J=12.0,8.2Hz,1H),7.05(dd,J=7.7,7.3Hz,1H),7.17-7.28(m,3H),7.42(dd,J=8.2,7.7Hz,1H)。 1 H-NMR (CDCl 3 ) δ: 1.07 (d, J = 6.3 Hz, 3H), 1.66 (s, 3H), 3.35 (dd, J = 30.4, 7.8 Hz, 1H), 3.75 (s, 6H), 3.81 (s, 6H), 3.85 (m, 1H), 4.45 (d, J = 15.9 Hz, 2H), 4.61 (d, J = 15.9 Hz, 2H), 5.38 (d, J = 48.6 Hz, 1H), 6.41-6.50 (m, 4H), 6.98 (dd, J = 12.0, 8.2 Hz, 1H), 7.05 (dd, J = 7.7, 7.3 Hz, 1H), 7.17-7.28 (m, 3H), 7.42 (dd, J = 8.2, 7.7 Hz, 1H).

步驟7 Step 7

在室溫下向化合物4-8(1.42g，2.49mmol)及九氟丁烷磺醯氟(1.61ml，8.96mmol)於甲苯(28ml)中之溶液中添加DBU(1.34ml，8.96mmol)。在室溫下攪拌12h之後，用NH4Cl飽和水溶液、水及2 mol/L HCl水溶液淬滅反應混合物。用AcOEt萃取水相且用2mol/LNaOH水溶液洗滌有機相。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物4-9及對應外烯烴之混合物(1.0g，化合物4-9：外烯烴=1：1，不可分離混合物)。 To a solution of compound 4-8 (1.42 g, 2.49 mmol) and EtOAc (EtOAc: EtOAc) After stirring at rt for 12h, with saturated aqueous NH 4 Cl, water, and 2 mol / L HCl aqueous reaction mixture was quenched. The aqueous phase was extracted with AcOEt and the organic phase was washed with 2 mol/L aqueous NaOH. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to give a mixture of compound 4-9 and corresponding external olefin (1.0 g, compound 4-9: external olefin = 1:1, insoluble mixture).

LC/MS(Shimadzu)：RT 1.98,MS計算值573.26(M+H+)，實驗值573.25。 </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI>

步驟8 Step 8

在室溫下向化合物4-9及外烯烴之混合物(1.0g，化合物4-9：外烯烴=1：1，不可分離混合物)及苯甲醚(1.34ml，12.2mmol)中添加TFA(6.73ml，87.0mmol)。在80℃下攪拌13.5h之後，將反應混合物冷卻至0℃且用K2CO3水溶液淬滅。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物4-10(251.8mg，925μmol，37%，2個步驟)。 Add TFA (6.73) to a mixture of compound 4-9 and an external olefin (1.0 g, compound 4-9: external olefin = 1:1, inseparable mixture) and anisole (1.34 ml, 12.2 mmol) at room temperature. Ml, 87.0 mmol). After stirring for 13.5 h at 80 ° C, the reaction mixture was cooled to 0 ° C and was quenched with aqueous K 2 CO 3 . The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to afford compound 4-10 (251.8 mg, 925.

1H-NMR(CDCl3)δ：1.40(dd,J=24.1,6.4Hz,3H),1.77(s,3H),3.89(ddd,J=30.2,12.9,7.8Hz,1H),4.88(ddq,J=49.0,7.8,6.4Hz,1H),5.25(d,J=47.2Hz,1H),7.10(dd,J=12.3,8.2Hz,1H),7.24(m,1H),7.32-7.45(m,2H)。 1 H-NMR (CDCl 3 ) δ: 1.40 (dd, J = 24.1, 6.4 Hz, 3H), 1.77 (s, 3H), 3.89 (ddd, J = 30.2, 12.9, 7.8 Hz, 1H), 4.88 (ddq) , J=49.0, 7.8, 6.4 Hz, 1H), 5.25 (d, J=47.2 Hz, 1H), 7.10 (dd, J = 12.3, 8.2 Hz, 1H), 7.24 (m, 1H), 7.32-7.45 ( m, 2H).

步驟9 Step 9

在-20℃下向化合物4-10(251.8mg，925μmol)於TFA(2.4ml)中之溶液中添加H2SO4(0.6ml)。在0℃下攪拌5分鐘之後，將反應混合物冷卻至-20℃且添加HNO3(62μl，1.39mmol)。在0℃下再攪拌30分鐘之後，用K2CO3水溶液淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物4-11(240.1mg，757μmol，82%)。 Solution of compound 4-10 (251.8mg, 925μmol) (2.4ml ) was added to the in TFA H 2 SO 4 (0.6ml) at -20 ℃. After stirring at 0 °C for 5 minutes, the reaction mixture was cooled to -20 ° C and HNO 3 (EtOAc, EtOAc, After stirring at 0 ° C for an additional 30 minutes, the reaction mixture was quenched with aqueous K 2 CO 3 . The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to afford compound 4-11 (240.1 mg, 757.

1H-NMR(CDCl3)δ：1.39(dd,J=24.2,6.4Hz,3H),1.65(s,3H),3.67(ddd,J=30.9,13.2,7.4Hz,1H),4.42(brs,2H),4.86(ddq,J= 48.8,7.4,6.4Hz,1H),5.15(d,J=47.7Hz,1H),7.23(m,1H),8.22(m,1H),8.45(m,1H)。 1 H-NMR (CDCl 3 ) δ: 1.39 (dd, J = 24.2, 6.4 Hz, 3H), 1.65 (s, 3H), 3.67 (ddd, J = 30.9, 13.2, 7.4 Hz, 1H), 4.42 (brs) , 2H), 4.86 (ddq, J = 48.8, 7.4, 6.4 Hz, 1H), 5.15 (d, J = 47.7 Hz, 1H), 7.23 (m, 1H), 8.22 (m, 1H), 8.45 (m, 1H).

步驟10 Step 10

在室溫下向化合物4-11(240.1mg，757μmol)及DMAP(18.5mg，151μmol)於CH2Cl2(2.4ml)中之溶液中添加Boc2O(439μl，1.89mmol)。在室溫下攪拌35分鐘之後，濃縮反應混合物。藉由矽膠層析純化殘餘物，獲得化合物4-12。自AcOEt/己烷濕磨殘餘物，得到化合物4-12(244.6mg，473μmol，62%)。化合物4-12之C7位置處之立體化學係藉由X射線結晶學分析測定。 Boc 2 O (439 μl, 1.89 mmol) was added to a solution of compound 4-11 (240.1 mg, 757 μmol) and DMAP (18.5 mg, 151 μmol) in CH 2 Cl 2 (2.4 ml). After stirring at room temperature for 35 minutes, the reaction mixture was concentrated. The residue was purified by silica gel chromatography to give compound 4-12. The residue was triturated from AcOEt / hexane to give compound 4-12 (244.6mg, 473 um, 62%). The stereochemistry at the C7 position of compounds 4-12 was determined by X-ray crystallographic analysis.

1H-NMR(CDCl3)δ：1.40(dd,J=24.1,6.5Hz,3H),1.52(s,18H),1.72(s,3H),3.80(ddd,J=29.9,12.9,7.2Hz,1H),4.91(ddq,J=48.1,7.2,6.5Hz,1H),5.19(d,J=47.2Hz,1H),7.28(m,1H),8.26(m,1H),8.57(m,1H)。 1 H-NMR (CDCl 3 ) δ: 1.40 (dd, J = 24.1, 6.5 Hz, 3H), 1.52 (s, 18H), 1.72 (s, 3H), 3.80 (ddd, J = 29.9, 12.9, 7.2 Hz , 1H), 4.91 (ddq, J=48.1, 7.2, 6.5 Hz, 1H), 5.19 (d, J = 47.2 Hz, 1H), 7.28 (m, 1H), 8.26 (m, 1H), 8.57 (m, 1H).

步驟11 Step 11

在室溫下向化合物4-12(241.2mg，466μmol)於THF(3ml)及MeOH(1.5ml)中之溶液中添加Pd/C(24.8mg)。在室溫下在H2氛圍下攪拌2h之後，經由矽藻土(註冊商標)墊過濾反應混合物且用AcOEt洗滌。濃縮濾液，且藉由矽膠層析純化殘餘物，獲得化合物4-13(214.2mg，439μmol，94%)。 To a solution of compound 4-12 (241.2 mg, 466 [mu]mol) in THF (3 mL) and MeOH (1. After stirring at room temperature for 2 h under H 2 atmosphere, the reaction mixture was filtered through a pad of Celite (registered trademark) and washed with AcOEt. The filtrate was concentrated, and the residue was purifiedjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

1H-NMR(CDCl3)δ：1.39(dd,J=24.1,6.4Hz,3H),1.52(s,18H),1.68(s,3H),3.58(brs,2H),3.91(ddd,J=30.0,13.4,7.4Hz,1H),4.88(ddq,J=48.8,7.4,6.4Hz,1H),5.16(d,J=47.7Hz,1H),6.56(m,1H),6.82-6.91(m,2H)。 1 H-NMR (CDCl 3 ) δ: 1.39 (dd, J = 24.1, 6.4 Hz, 3H), 1.52 (s, 18H), 1.68 (s, 3H), 3.58 (brs, 2H), 3.91 (ddd, J) =30.0,13.4,7.4 Hz,1H), 4.88 (ddq, J=48.8, 7.4, 6.4 Hz, 1H), 5.16 (d, J=47.7 Hz, 1H), 6.56 (m, 1H), 6.82-6.91 ( m, 2H).

步驟12 Step 12

在室溫下向化合物4-13(70.0mg，144μmol)、5-氰基吡啶甲酸水合物(28.6mg，172μmol)及二異丙基乙胺(50μl，287μmol)於DMF(1 ml)中之溶液中添加HATU(65.5mg，172μmol)。在室溫下攪拌1.5h之後，用NH4Cl飽和水溶液淬滅反應混合物。用AcOEt萃取水相，且用H2O洗滌有機相。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物4-14(90.0mg，定量)。 Compound 4-13 (70.0 mg, 144 μmol), 5-cyanopyridinecarboxylic acid hydrate (28.6 mg, 172 μmol) and diisopropylethylamine (50 μl, 287 μmol) in DMF (1 ml) at room temperature HATU (65.5 mg, 172 μmol) was added to the solution. After stirring for 1.5h at room temperature, saturated aqueous NH 4 Cl the reaction mixture was quenched. The aqueous phase was extracted with AcOEt, and H 2 O and the organic phase was washed. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to afford compound 4-14 (90.0 mg, quantitative).

1H-NMR(CDCl3)δ：1.40(dd,J=24.0,6.4Hz,3H),1.56(s,18H),1.75(s,3H),3.90(ddd,J=30.6,13.2,7.4Hz,1H),4.89(ddq,J=48.8,7.4,6.4Hz,1H),5.18(d,J=47.3Hz,1H),7.15(m,1H),7.60(m,1H),8.21(d,J=8.3Hz,1H),8.40(m,1H),8.43(d,J=8.3Hz,1H),8.80(s,1H),9.99(s,1H)。 1 H-NMR (CDCl 3) δ: 1.40 (dd, J = 24.0,6.4Hz, 3H), 1.56 (s, 18H), 1.75 (s, 3H), 3.90 (ddd, J = 30.6,13.2,7.4Hz , 1H), 4.89 (ddq, J = 48.8, 7.4, 6.4 Hz, 1H), 5.18 (d, J = 47.3 Hz, 1H), 7.15 (m, 1H), 7.60 (m, 1H), 8.21 (d, J = 8.3 Hz, 1H), 8.40 (m, 1H), 8.43 (d, J = 8.3 Hz, 1H), 8.80 (s, 1H), 9.99 (s, 1H).

步驟13 Step 13

將化合物4-14(90.0mg，144μmol)溶解於甲酸(1ml)中且在室溫下攪拌16h。用K2CO3水溶液淬滅反應混合物，且用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。自AcOEt/己烷濕磨殘餘物，得到化合物I-13(48.8mg，117μmol，2個步驟中之81%)。 Compound 4-14 (90.0 mg, 144 [mu]mol) was dissolved in EtOAc (1 mL). With K 2 CO 3 solution the reaction mixture was quenched, and the aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was triturated from AcOEt / hexane to afford compound I-13 (48.8 mg, 117 [mu]mol, 81% of 2 steps).

實例5 合成化合物I-16 Example 5 Synthesis of Compound I-16

步驟1 step 1

在0℃下向碘(1.05g，4.15mmol)於乙腈(45ml)中之溶液中添加乙腈(15ml)中之化合物4-6(1.15g，2.07mmol)。在0℃下攪拌3天之後，用NaHCO3飽和水溶液淬滅反應混合物，接著添加Na2S2O3水溶 液。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物5-1(1.20g，1.76mmol，85%)。 To a solution of iodine (1.05 g, 4.15 mmol) in EtOAc (45 mL) EtOAc (EtOAc) After stirring at 0 ℃ 3 days with saturated aqueous NaHCO 3 to quench the reaction mixture, followed by addition of Na 2 S 2 O 3 aq. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to afford compound 5-1 (1.20 g, 1.76 mmol, 85%).

1H-NMR(CDCl3)δ：1.65(s,3H),1.74(d,J=6.8Hz,3H),3.61(dd,J=27.5,10.0Hz,1H),3.74(s,6H),3.81(s,6H),4.10(m,1H),4.45(d,J=16.1Hz,2H),4.61(d,J=16.1Hz,2H),5.66(d,J=48.3Hz,1H),6.41-6.49(m,4H),7.03(m,1H),7.06(m,1H),7.19(d,J=8.2Hz,2H),7.22(m,1H),7.41(m,1H)。 1 H-NMR (CDCl 3 ) δ: 1.65 (s, 3H), 1.74 (d, J = 6.8 Hz, 3H), 3.61 (dd, J = 27.5, 10.0 Hz, 1H), 3.74 (s, 6H), 3.81 (s, 6H), 4.10 (m, 1H), 4.45 (d, J = 16.1 Hz, 2H), 4.61 (d, J = 16.1 Hz, 2H), 5.66 (d, J = 48.3 Hz, 1H), 6.41-6.49 (m, 4H), 7.03 (m, 1H), 7.06 (m, 1H), 7.19 (d, J = 8.2 Hz, 2H), 7.22 (m, 1H), 7.41 (m, 1H).

步驟2 Step 2

在室溫下向18-crown-6(1.62g，6.11mmol)及KO2(435mg，6.11mmol)於DMSO(25ml)中之溶液中添加DMSO(15ml)中之化合物5-1(1.04g，1.53mmol)。在攪拌30分鐘之後，在0℃下用Na2S2O3飽和水溶液淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物5-2(291mg，510μmol，33%)。 To a solution of 18-crown-6 (1.62 g, 6.11 mmol) and KO 2 (435 mg, 6.11 mmol) in EtOAc (25 mL) 1.53 mmol). After stirring for 30 minutes, the reaction mixture was quenched with a saturated aqueous Na 2 S 2 O 3 at 0 °C. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to afford compound 5-2 (291 mg, 510.

1H-NMR(CDCl3)δ：1.07(d,J=6.3Hz,3H),1.62(s,3H),2.25(brs,1H),3.34(dd,J=30.9,8.0Hz,1H),3.76(s,6H),3.81(s,6H),3.83(m,1H),4.49(d,J=15.9Hz,2H),4.67(d,J=15.9Hz,2H),5.14(d,J=48.8Hz,1H),6.42-6.51(m,4H),6.98(m,1H),7.03(m,1H),7.17-7.29(m,3H),7.37(m,1H)。 1 H-NMR (CDCl 3 ) δ: 1.07 (d, J = 6.3 Hz, 3H), 1.62 (s, 3H), 2.25 (brs, 1H), 3.34 (dd, J = 30.9, 8.0 Hz, 1H), 3.76 (s, 6H), 3.81 (s, 6H), 3.83 (m, 1H), 4.49 (d, J = 15.9 Hz, 2H), 4.67 (d, J = 15.9 Hz, 2H), 5.14 (d, J) = 48.8 Hz, 1H), 6.42 - 6.51 (m, 4H), 6.98 (m, 1H), 7.03 (m, 1H), 7.17-7.29 (m, 3H), 7.37 (m, 1H).

步驟3 Step 3

在-65℃下向化合物5-2(290mg，508μmol)於CH2Cl2(6ml)中之溶液中添加DAST(537μl，4.06mmol)。在室溫下攪拌22.5h之後，在0℃下用NaHCO3飽和水溶液淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物5-3及對應內烯烴之混合物(212mg，化合物5-3：內烯烴=2.5：1，不可分離混合物)。化合物5-3之產率藉由1H NMR比率計算為53%。 DAST was added to the compound of 5-2 (290mg, 508μmol) in CH 2 Cl 2 (6ml) solution at -65 ℃ (537μl, 4.06mmol). After 22.5h stirring at room temperature, at 0 ℃ reaction mixture was quenched with saturated aqueous NaHCO 3. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to give a mixture of compound 5-3 and corresponding internal olefin (212 mg, compound 5-3: internal olefin = 2.5:1, insoluble mixture). The yield of the compound 5-3 was calculated to be 53% by the 1 H NMR ratio.

1H-NMR(CDCl3)δ：1.17(dd,J=25.5,6.1Hz,3H),1.66(s,3H),3.53(m,1H),3.75(s,6H),3.81(s,6H),4.38-4.75(m,5H),5.30(d,J=48.3Hz,1H),6.40-6.50(m,4H),7.00(m,1H),7.06(m,1H),7.15-7.29(m,3H),7.41(m,1H)。 1 H-NMR (CDCl 3 ) δ: 1.17 (dd, J = 25.5, 6.1 Hz, 3H), 1.66 (s, 3H), 3.53 (m, 1H), 3.75 (s, 6H), 3.81 (s, 6H) ), 4.38-4.75 (m, 5H), 5.30 (d, J = 48.3 Hz, 1H), 6.40-6.50 (m, 4H), 7.00 (m, 1H), 7.06 (m, 1H), 7.15-7.29 ( m, 3H), 7.41 (m, 1H).

步驟4 Step 4

在室溫下向化合物5-3及外烯烴之混合物(5-3之淨重：172mg，300μmol)及苯甲醚(316μl，2.89mmol)中添加TFA(1.59ml，20.7mmol)。在80℃下攪拌17h之後，將反應混合物冷卻至0℃且用K2CO3水溶液淬滅。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物5-4(103mg，定量)。 To a mixture of compound 5-3 and an external olefin (net weight of 5-3: 172 mg, 300 μmol) and anisole (316 μl, 2.89 mmol) were added TFA (1.59 ml, 20.7 mmol) at room temperature. After stirring for 17h at 80 ℃, the reaction mixture was cooled to 0 ℃ and treated with K 2 CO 3 solution was quenched. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to afford Compound 5-4 (103 mg, quantitative).

1H-NMR(CDCl3)δ：1.44(dd,J=25.3,6.0Hz,3H),1.85(s,3H),3.84(m,1H),4.86(m,1H),5.44(d,J=46.4Hz,1H),7.12(m,1H),7.26(m,1H),7.33-7.43(m,2H)。 1 H-NMR (CDCl 3) δ: 1.44 (dd, J = 25.3,6.0Hz, 3H), 1.85 (s, 3H), 3.84 (m, 1H), 4.86 (m, 1H), 5.44 (d, J = 46.4 Hz, 1H), 7.12 (m, 1H), 7.26 (m, 1H), 7.33-7.43 (m, 2H).

步驟5 Step 5

在-20℃下向化合物5-4(103mg，300μmol)於TFA(1.2ml)中之溶液中添加H2SO4(0.3ml)。在0℃下攪拌5分鐘之後，將反應混合物冷卻至-20℃且添加HNO3(25μl，567μmol)。在0℃下攪拌30分鐘之後，用K2CO3水溶液淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物5-5(86.3mg，272μmol，91%，2個步驟)。 Solution of compound 5-4 (103mg, 300μmol) (1.2ml ) was added to the in TFA H 2 SO 4 (0.3ml) at -20 ℃. After stirring at 0 ° C for 5 minutes, the reaction mixture was cooled to -20 ° C and HNO 3 (25 μl, 567 μmol) was added. After stirring for 30 minutes at 0 ℃, with K 2 CO 3 solution the reaction mixture was quenched. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to afford compound 5-5 (86.3 mg, 272.

1H-NMR(CDCl3)δ：1.40(dd,J=25.5,6.1Hz,3H),1.67(s,3H),3.53(m,1H),4.29(brs,2H),4.81(m,1H),5.30(d,J=47.2Hz,1H),7.23(m,1H),8.21(m,1H),8.44(m,1H)。 1 H-NMR (CDCl 3) δ: 1.40 (dd, J = 25.5,6.1Hz, 3H), 1.67 (s, 3H), 3.53 (m, 1H), 4.29 (brs, 2H), 4.81 (m, 1H ), 5.30 (d, J = 47.2 Hz, 1H), 7.23 (m, 1H), 8.21 (m, 1H), 8.44 (m, 1H).

步驟6 Step 6

在室溫下向化合物5-5(86.3mg，272μmol)及DMAP(16.6mg，135μmol)於CH2Cl2(2ml)中之溶液中添加Boc2O(158μl，680 μmol)。在室溫下攪拌50分鐘之後，濃縮反應混合物。藉由矽膠層析純化殘餘物，獲得化合物5-6(129mg，248μmol，91%)。 Boc 2 O (158 μl, 680 μmol) was added to a solution of compound 5-5 (86.3 mg, 272 μmol) and DMAP (16.6 mg, 135 μmol) in CH 2 Cl 2 (2 ml). After stirring at room temperature for 50 minutes, the reaction mixture was concentrated. The residue was purified by silica gel chromatography to afford compound 5-6 (129 mg, 248.

1H-NMR(CDCl3)δ：1.41(dd,J=25.5,6.1Hz,3H),1.53(s,18H),1.74(s,3H),3.65(ddd,J=27.4,8.3,4.8Hz,1H),4.87(ddq,J=46.7,8.3,6.1Hz,1H),5.35(d,J=46.9Hz,1H),7.27(m,1H),8.26(m,1H),8.52(m,1H)。 1 H-NMR (CDCl 3 ) δ: 1.41 (dd, J = 25.5, 6.1 Hz, 3H), 1.53 (s, 18H), 1.74 (s, 3H), 3.65 (ddd, J = 27.4, 8.3, 4.8 Hz , 1H), 4.87 (ddq, J = 46.7, 8.3, 6.1 Hz, 1H), 5.35 (d, J = 46.9 Hz, 1H), 7.27 (m, 1H), 8.26 (m, 1H), 8.52 (m, 1H).

步驟7 Step 7

在室溫下向化合物5-6(129mg，248μmol)於THF(2ml)及MeOH(1ml)中之溶液中添加Pd/C(26.4mg)。在室溫下在H2氛圍下攪拌7.5h之後，經由矽藻土(註冊商標)墊過濾反應混合物且用AcOEt洗滌。濃縮濾液，且藉由矽膠層析純化殘餘物，獲得化合物5-7(104mg，214μmol，86%)。 To a solution of compound 5-6 (129 mg, 248 [mu]mol) in THF (2 mL) MeOH (1 mL) After stirring at room temperature for 7.5 h under H 2 atmosphere, the reaction mixture was filtered through a pad of Celite (trademark) and washed with AcOEt. The filtrate was concentrated, and the residue was purifiedjjjjjjjjjjjjj

1H-NMR(CDCl3)δ：1.40(dd,J=25.4,6.1Hz,3H),1.53(s,18H),1.70(s,3H),3.56(brs,2H),3.80(m,1H),4.84(m,1H),5.33(d,J=47.3Hz,1H),6.56(m,1H),6.83(m,1H),6.86(m,1H)。 1 H-NMR (CDCl 3 ) δ: 1.40 (dd, J = 25.4, 6.1 Hz, 3H), 1.53 (s, 18H), 1.70 (s, 3H), 3.56 (brs, 2H), 3.80 (m, 1H) ), 4.84 (m, 1H), 5.33 (d, J = 47.3 Hz, 1H), 6.56 (m, 1H), 6.83 (m, 1H), 6.86 (m, 1H).

步驟8 Step 8

在室溫下向化合物5-7(44.2mg，90.7μmol)、5-(氟甲氧基)吡-2-甲酸(18.7mg，109μmol)及二異丙基乙胺(32μl，181μmol)於DMF(1ml)中之溶液中添加HATU(41.4mg，109μmol)。在室溫下攪拌50分鐘之後，用NH4Cl飽和水溶液淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物5-8(51.6mg，80.4μmol，89%)。 To compound 5-7 (44.2 mg, 90.7 μmol), 5-(fluoromethoxy)pyridine at room temperature HATU (41.4 mg, 109 μmol) was added to a solution of 2-carboxylic acid (18.7 mg, 109 μmol) and diisopropylethylamine (32 μl, 181 μmol) in DMF (1 mL). After stirring at room temperature for 50 minutes, treated with saturated aqueous NH 4 Cl the reaction mixture was quenched. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to afford compound 5-8 (51.6 mg, 80.4.

1H-NMR(CDCl3)δ：1.40(dd,J=25.3,6.1Hz,3H),1.54(s,18H),1.76(s,3H),3.78(m,1H),4.85(m,1H),5.36(d,J=47.2Hz,1H),6.15(dd,J=51.1,14.8Hz,2H),7.14(m,1H),7.47(m,1H),8.20(s,1H),8.35(m,1H),9.08(s,1H),9.62(s,1H)。 1 H-NMR (CDCl 3 ) δ: 1.40 (dd, J = 25.3, 6.1 Hz, 3H), 1.54 (s, 18H), 1.76 (s, 3H), 3.78 (m, 1H), 4.85 (m, 1H) ), 5.36 (d, J = 47.2 Hz, 1H), 6.15 (dd, J = 51.1, 14.8 Hz, 2H), 7.14 (m, 1H), 7.47 (m, 1H), 8.20 (s, 1H), 8.35 (m, 1H), 9.08 (s, 1H), 9.62 (s, 1H).

步驟9 Step 9

將化合物5-8(51.6mg，80.4μmol)溶解於甲酸(0.75ml)中且在室溫下攪拌18.5h。在0℃下用K2CO3水溶液淬滅反應混合物，且用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。自AcOEt/己烷濕磨殘餘物，得到化合物I-16(31.0mg，70.2μmol，87%)。 Compound 5-8 (51.6 mg, 80.4 μmol) was dissolved in formic acid (0.75 ml) and stirred at room temperature for 18.5 h. The reaction mixture was quenched with aqueous K 2 CO 3 at 0 ° C and aqueous was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was triturated from AcOEt / hexane to afford compound I-16 (31.0 mg, 70.2.

實例6 合成化合物I-28 Example 6 Synthesis of Compound I-28

步驟1 step 1

在-78℃下向二異丙胺(37.7mL，0.265mol)於THF(260mL)中之攪拌溶液中逐滴添加正丁基鋰(己烷中之2.65mol/L，100mL，0.265mol)。在0℃下攪拌25分鐘之後，在-78℃下向混合物中逐滴添加丙酸乙酯(30.4mL，0.265mol)，接著添加THF(70mL)中之氯三異丙氧基鈦(IV)(84.0mL，0.353mol)。在-78℃下攪拌30分鐘之後，將THF(70mL)中之化合物6-1(21.3g，0.088mol)逐滴添加至混合物中。將反應混合物在-78℃下攪拌30分鐘。用氯化銨飽和溶液淬滅反應物。經矽藻土(註冊商標)過濾所得混合物，且用乙酸乙酯萃取濾液。用鹽水洗滌經合併之有機層，經硫酸鈉乾燥且過濾。蒸發溶劑，且藉由急驟管柱層析(矽膠，3：1至1：1己烷：乙酸乙酯之梯度)純化粗產物，得到呈茶 色油狀之化合物6-2(24.8g，82%)。以非對映異構體之混合物形式獲得此材料。 n-Butyllithium (2.65 mol/L in hexane, 100 mL, 0.265 mol) was added dropwise to a stirred solution of diisopropylamine (37.7 mL, 0.265 mol) in THF (260 mL). After stirring at 0 ° C for 25 minutes, ethyl propionate (30.4 mL, 0.265 mol) was added dropwise to the mixture at -78 ° C, followed by the addition of titanium triisopropoxide (IV) in THF (70 mL). (84.0 mL, 0.353 mol). After stirring at -78 °C for 30 minutes, compound 6-1 (21.3 g, 0.088 mol) in THF (70 mL) was added dropwise to the mixture. The reaction mixture was stirred at -78 °C for 30 minutes. The reaction was quenched with a saturated solution of ammonium chloride. The resulting mixture was filtered through celite (registered trademark), and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was evaporated, and the crude product was purified by flash column chromatography (3:1 to 1:1 hexane: ethyl acetate) Compound 6-2 (24.8 g, 82%). This material is obtained as a mixture of diastereomers.

1H NMR(400MHz,CDCl3)(主要異構體)1.14(d,J=7.0Hz,3H),1.28(s,9H),1.95(s,3H),3.14(q,J=7.0Hz,1H),3.98-4.04(m,1H),4.89(s,1H),7.01-7.43(m,5H)。 1 H NMR (400 MHz, CDCl 3 ) (major isomer) 1.14 (d, J = 7.0 Hz, 3H), 1.28 (s, 9H), 1.95 (s, 3H), 3.14 (q, J = 7.0 Hz, 1H), 3.98-4.04 (m, 1H), 4.89 (s, 1H), 7.01-7.43 (m, 5H).

步驟2 Step 2

在-78℃下向二異丙胺(37.7mL，0.265mol)於THF(260mL)中之攪拌溶液中逐滴添加正丁基鋰(己烷中之2.65mol/L，100mL，0.265mol)。在0℃下攪拌25分鐘之後，在-78℃下向混合物中逐滴添加丙酸乙酯(30.4mL，0.265mol)，接著添加THF(70mL)中之氯三異丙氧基鈦(IV)(84.0mL，0.353mol)。在-78℃下攪拌30分鐘之後，將THF(70mL)中之化合物6-1(21.3g，0.088mol)逐滴添加至混合物中。將反應混合物在-78℃下攪拌30分鐘。用氯化銨飽和溶液淬滅反應物。經矽藻土(註冊商標)過濾所得混合物，且用乙酸乙酯萃取濾液。用鹽水洗滌經合併之有機層，經硫酸鈉乾燥且過濾。蒸發溶劑，且藉由急驟管柱層析(矽膠，3：1至1：1己烷：乙酸乙酯之梯度)純化粗產物，得到呈茶色油狀之化合物6-2(24.8g，82%)。以非對映異構體之混合物形式獲得此材料。 n-Butyllithium (2.65 mol/L in hexane, 100 mL, 0.265 mol) was added dropwise to a stirred solution of diisopropylamine (37.7 mL, 0.265 mol) in THF (260 mL). After stirring at 0 ° C for 25 minutes, ethyl propionate (30.4 mL, 0.265 mol) was added dropwise to the mixture at -78 ° C, followed by the addition of titanium triisopropoxide (IV) in THF (70 mL). (84.0 mL, 0.353 mol). After stirring at -78 °C for 30 minutes, compound 6-1 (21.3 g, 0.088 mol) in THF (70 mL) was added dropwise to the mixture. The reaction mixture was stirred at -78 °C for 30 minutes. The reaction was quenched with a saturated solution of ammonium chloride. The resulting mixture was filtered through celite (registered trademark), and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was evaporated, and the title compound was purified mjjjjjjjjj ). This material is obtained as a mixture of diastereomers.

1H NMR(400MHz,CDCl3)1.06(d,J=7.5Hz,3H),1.20(s,9H),1.84(s,3H),3.36(q,J=7.5Hz,1H),4.99(s,1H),7.02-7.45(m,4H),9.76(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) 1.06 (d, J = 7.5 Hz, 3H), 1.20 (s, 9H), 1.84 (s, 3H), 3.36 (q, J = 7.5 Hz, 1H), 4.99 (s) , 1H), 7.02-7.45 (m, 4H), 9.76 (s, 1H).

在氮氣氛圍下，在0℃下向化合物6-3(1.04g，3.47mmol)於THF(20mL)中之攪拌溶液中添加三甲基(三氟甲基)矽烷(1.05mL，6.95mmol)及TBAF(THF中之1mol/L，0.243mL，0.243mmol)。在0℃下攪拌1h之後，用水淬滅反應物。用乙酸乙酯萃取混合物。用鹽水洗滌經合併之有機層，經硫酸鈉乾燥且過濾。蒸發溶劑，得到粗產物， 其不經進一步純化即用於下一反應。 Trimethyl(trifluoromethyl)decane (1.05 mL, 6.95 mmol) was added to a stirred solution of compound 6-3 (1.04 g, 3.47 mmol) in THF (20 mL) TBAF (1 mol/L in THF, 0.243 mL, 0.243 mmol). After stirring at 0 °C for 1 h, the reaction was quenched with water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was evaporated to give a crude product. It was used in the next reaction without further purification.

在0℃下向粗產物於甲醇(15mL)中之攪拌溶液中添加氯化氫(二烷中之4mol/L，1.30mL，5.20mmol)。在室溫下攪拌20h之後，用碳酸氫鈉飽和溶液淬滅反應物。用乙酸乙酯萃取混合物。用鹽水洗滌經合併之有機層，經硫酸鈉乾燥且過濾。蒸發溶劑，得到粗產物，其不經進一步純化即用於下一反應。 Add hydrogen chloride to the stirred solution of the crude product in methanol (15 mL) at 0 ° C (two 4 mol/L in the alkane, 1.30 mL, 5.20 mmol). After stirring at room temperature for 20 h, the reaction was quenched with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was evaporated to give a crude material.

在0℃下向粗產物於二氯甲烷(15mL)中之攪拌溶液中添加異硫氰酸苯甲醯酯(0.559mL，4.16mmol)。在室溫下攪拌2.5h之後，蒸發混合物。藉由急驟管柱層析(矽膠，3：1己烷：乙酸乙酯)純化粗產物，得到呈黃色非晶形形式之化合物6-4(620mg，42%)。以非對映異構體之混合物形式獲得此材料。Ms：m/z=595.10[M+H]+。 To a stirred solution of the crude product in dichloromethane (15 mL), EtOAc (EtOAc) After stirring at room temperature for 2.5 h, the mixture was evaporated. The crude product was purified by flash column chromatography eluting elut elut elut elut elut This material is obtained as a mixture of diastereomers. Ms: m/z = 595.10 [M+H] + .

步驟4 Step 4

在室溫下攪拌化合物6-4(620mg，1.45mmol)及WSCD．HCl(555mg，2.89mmol)於乙腈(12mL)中之懸浮液20h。添加水至反應混合物中，其隨後用乙酸乙酯萃取。用鹽水洗滌經合併之有機層，經硫酸鈉乾燥且過濾。蒸發溶劑，且藉由急驟管柱層析(矽膠，85：15己烷：乙酸乙酯)純化粗產物，得到呈無色油狀之化合物6-5(258mg，45%)。 Compound 6-4 (620 mg, 1.45 mmol) and WSCD were stirred at room temperature. A suspension of HCl (555 mg, 2.89 mmol) in EtOAc (EtOAc) Water was added to the reaction mixture which was subsequently extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was evaporated, and the title compound wasjjjjjjjjjjjjj

1H NMR(400MHz,CDCl3)1.30(d,J=6.9Hz,3H),1.79(s,3H),2.96(q,J=6.9Hz,1H),4.35-4.39(m,1H),7.13-7.55(m,7H),8.27(d,J=8.0Hz,2H),11.6(s,1H)。 1 H NMR (400MHz, CDCl 3 ) 1.30 (d, J = 6.9Hz, 3H), 1.79 (s, 3H), 2.96 (q, J = 6.9Hz, 1H), 4.35-4.39 (m, 1H), 7.13 -7.55 (m, 7H), 8.27 (d, J = 8.0 Hz, 2H), 11.6 (s, 1H).

步驟5 Step 5

在室溫下攪拌化合物6-5(258mg，0.654mmol)及碳酸鉀(271mg，1.96mmol)於甲醇(5mL)中之懸浮液3天。添加水至反應混合物中，其隨後用乙酸乙酯萃取。用鹽水洗滌經合併之有機層，經硫酸鈉乾燥且過濾。蒸發溶劑，得到粗產物，其不經進一步純化即用於下一反應。 A suspension of compound 6-5 (258 mg, 0.654 mmol) and potassium carbonate (271 mg, 1.96 mmol) in methanol (5 mL) Water was added to the reaction mixture which was subsequently extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was evaporated to give a crude material.

在-20℃下向粗產物於TFA(1.1mL)中之攪拌溶液中添加硫酸(0.28mL，5.25mmol)，接著添加硝酸(0.044mL，0.982mmol)。在-20℃至-10℃下攪拌75分鐘之後，用碳酸鉀飽和溶液淬滅反應物。用乙酸乙酯萃取混合物。用鹽水洗滌經合併之有機層，經硫酸鈉乾燥且過濾。蒸發溶劑，且藉由急驟管柱層析(矽膠，2：1至1：1己烷：乙酸乙酯之梯度)純化粗產物，得到呈無色非晶形形式之化合物6-6(149mg，68%) Sulfuric acid (0.28 mL, 5.25 mmol) was added to a stirred solution of EtOAc (EtOAc) (EtOAc). After stirring at -20 ° C to -10 ° C for 75 minutes, the reaction was quenched with a saturated solution of potassium carbonate. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was evaporated, and the crude material was purified mjjjjjjjjjjj )

1H NMR(400MHz,CDCl3)1.19(d,J=7.0Hz,3H),2.74(q,J=7.0Hz,1H),3.99-4.04(m,1H),7.22(t,J=9.9Hz,1H),8.17-8.21(m,1H),8.35(dd,J=6.7,2.8Hz,1H)。 1 H NMR (400MHz, CDCl 3 ) 1.19 (d, J = 7.0Hz, 3H), 2.74 (q, J = 7.0Hz, 1H), 3.99-4.04 (m, 1H), 7.22 (t, J = 9.9Hz , 1H), 8.17-8.21 (m, 1H), 8.35 (dd, J = 6.7, 2.8 Hz, 1H).

步驟6 Step 6

在60℃下攪拌化合物6-6(85.7mg，0.256mmol)、鐵粉(114mg，2.05mmol)及氯化銨(164mg，3.07mmol)於乙醇(0.8mL)/THF(0.4mL)/水(0.4mL)中之懸浮液2.5h。將混合物冷卻至室溫且經由矽藻土(註冊商標)墊過濾。濾液用乙酸乙酯萃取。用鹽水洗滌經合併之有機層，經硫酸鈉乾燥且過濾。蒸發溶劑，得到粗產物，其不經進一步純化即用於下一反應。 Compound 6-6 (85.7 mg, 0.256 mmol), iron powder (114 mg, 2.05 mmol) and ammonium chloride (164 mg, 3.07 mmol) in ethanol (0.8 mL) / THF (0.4 mL) / water. The suspension in 0.4 mL) was 2.5 h. The mixture was cooled to room temperature and filtered through a pad of Celite (registered trademark). The filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was evaporated to give a crude material.

在室溫下向粗產物及鹽酸水溶液(2mol/L，0.081mL，0.161mmol)於甲醇(1mL)中之攪拌溶液中添加5-氰基吡啶甲酸水合物(29.5mg，0.177mmol)及WSCD．HCl(37.1mg，0.161mmol)。在室溫下攪拌1h之後，用氫氧化鈉水溶液淬滅反應物。用乙酸乙酯萃取混合物。用鹽水洗滌經合併之有機層，經硫酸鈉乾燥且過濾。蒸發溶劑，且藉由急驟管柱層析(胺基矽膠，1：1至0：1己烷：乙酸乙酯之梯度)純化粗產物，得到呈灰白色固體之化合物I-28(58.1mg，74%)。 To a stirred solution of the crude product and aqueous hydrochloric acid (2 mol/L, 0.081 mL, 0.161 mmol) in methanol (1 mL) was added 5-cyanopyridinecarboxylic acid hydrate (29.5 mg, 0.177 mmol) and WSCD. HCl (37.1 mg, 0.161 mmol). After stirring at room temperature for 1 h, the reaction was quenched with aqueous sodium hydroxide. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was evaporated, and the title compound was purified mjjjjjjjjj %).

實例7 合成化合物I-33 Example 7 Synthesis of Compound I-33

[化學式58] [Chemical Formula 58]

步驟1 step 1

在室溫下攪拌化合物7-1(6.2g，18.1mmol)(用於合成I-28之中間物)及氯化氫溶液(二烷中之4mol/L，6.77mL，27.1mmol)於甲醇(45mL)中之溶液75分鐘。用碳酸氫鈉飽和溶液淬滅反應物。用乙酸乙酯萃取混合物。用鹽水洗滌經合併之有機層，經硫酸鈉乾燥且過濾。蒸發溶劑，得到粗產物，其不經進一步純化即用於下一反應。 Stir compound 7-1 (6.2 g, 18.1 mmol) (for the synthesis of intermediates of I-28) and hydrogen chloride solution at room temperature (two A solution of 4 mol/L, 6.77 mL, 27.1 mmol) in methanol (45 mL) was applied for 75 min. The reaction was quenched with a saturated solution of sodium bicarbonate. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was evaporated to give a crude material.

在室溫下攪拌粗產物及Boc2O(5.79mL，27.1mmol)於THF(40mL)中之溶液16h，接著加熱至50℃後維持24h。將混合物冷卻至室溫且蒸發。藉由急驟管柱層析(矽膠，9：1己烷：乙酸乙酯)純化粗產 物，得到呈茶色油狀之化合物7-2(5.7g，93%)。以非對映異構體之混合物形式獲得此材料。 The crude product and a solution of Boc 2 O (5.79 mL, 27.1 mmol) in THF (40 mL) The mixture was cooled to room temperature and evaporated. The crude product was purified by flash chromatography eluting elut elut elut elut elut elut elut This material is obtained as a mixture of diastereomers.

1H NMR(400MHz,CDCl3)(主要異構體)0.96(d,J=7.0Hz,3H),1.23(t,J=6.4Hz),1.40(s,9H),1.91(s,3H),3.01(q,J=7.0Hz,1H),4.10-4.16(m,3H),5.95(1H,brs),6.97-7.31(m,5H)。 1 H NMR (400 MHz, CDCl 3 ) (major isomer) 0.96 (d, J = 7.0 Hz, 3H), 1.23 (t, J = 6.4 Hz), 1.40 (s, 9H), 1.91 (s, 3H) , 3.01 (q, J = 7.0 Hz, 1H), 4.10 - 4.16 (m, 3H), 5.95 (1H, brs), 6.97 - 7.31 (m, 5H).

步驟2 Step 2

在0℃下向化合物7-2(5.12g，15.1mmol)於THF(25mL)及甲醇(25mL)中之攪拌溶液中緩慢添加硼氫化鈉(2.85g，75.0mmol)。在0℃下攪拌2h之後，在0℃下將硼氫化鈉(2.85g，75.0mmol)緩慢添加至混合物中。在室溫下攪拌所得混合物16.5h。用氯化氫水溶液淬滅反應物。用乙酸乙酯萃取混合物。用鹽水洗滌經合併之有機層，經硫酸鈉乾燥且過濾。蒸發溶劑，得到粗產物，其不經進一步純化即用於下一反應。 Sodium borohydride (2.85 g, 75.0 mmol) was slowly added to a stirred solution of Compound 7-2 (5.12 g, 15.1 mmol) in THF (25 mL) After stirring at 0 °C for 2 h, sodium borohydride (2.85 g, 75.0 mmol) was slowly added to the mixture at 0 °C. The resulting mixture was stirred at room temperature for 16.5 h. The reaction was quenched with aqueous hydrogen chloride. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was evaporated to give a crude material.

在氮氣氛圍下，在0℃下向粗產物於二氯甲烷(50mL)中之攪拌溶液中添加戴斯-馬丁(Dess-Martin)高碘烷(9.54g，22.5mmol)。在室溫下攪拌4.5h之後，用碳酸氫鈉及硫代硫酸鈉飽和溶液淬滅反應物。用二氯甲烷萃取混合物。經硫酸鈉乾燥經合併之有機層且過濾。蒸發溶劑，且藉由急驟管柱層析(矽膠，1：1至1：2己烷：乙酸乙酯之梯度)純化粗產物，得到呈無色膠狀物狀之化合物7-3(2.15g，49%)。以非對映異構體之混合物形式獲得此材料。 Dess-Martin periodinane (9.54 g, 22.5 mmol) was added to a stirred solution of the crude material in dichloromethane (50 mL). After stirring at room temperature for 4.5 h, the reaction was quenched with sodium bicarbonate and sodium thiosulphate. The mixture was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and filtered. The solvent was evaporated, and the title compound was purified mjjjjjjjj 49%). This material is obtained as a mixture of diastereomers.

1H NMR(400MHz,CDCl3)(主要異構體)1.02(d,J=6.9Hz,3H),1.97(s,3H),3.15-3.20(m,1H),5.16(s,1H),7.00-7.33(5H,m),9.71(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) (major isomer) 1.02 (d, J = 6.9 Hz, 3H), 1.97 (s, 3H), 3.15-3.20 (m, 1H), 5.16 (s, 1H), 7.00-7.33 (5H, m), 9.71 (s, 1H).

步驟3 Step 3

在回流下攪拌化合物7-3(2.15g，7.28mmol)及惠寧氏鹼(Hunig's base)(6.36mL，36.4mmol)於THF(10mL)中之溶液25.5h。將混合物 冷卻至室溫，且蒸發溶劑。藉由急驟管柱層析(矽膠，87：13至85：15己烷：乙酸乙酯之梯度)純化粗產物，得到呈無色膠狀物狀之化合物7-4(1.81g，84%)。以非對映異構體之混合物形式獲得此材料。 A solution of compound 7-3 (2.15 g, 7.28 mmol) and Hunig's base (6.36 mL, 36.4 mmol) in THF (10 mL). Mixture Cool to room temperature and evaporate the solvent. The crude product was purified by flash chromatography eluting elut elut elut elut elut elut elut elut elut This material is obtained as a mixture of diastereomers.

1H NMR(400MHz,CDCl3)(主要異構體)1.12(d,J=6.9Hz,3H),1.76(s,3H),3.09-3.14(m,1H),5.17(s,1H),7.02-7.33(5H,m),9.57(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) (major isomer) 1.12 (d, J = 6.9 Hz, 3H), 1.76 (s, 3H), 3.09 - 3.14 (m, 1H), 5.17 (s, 1H), 7.02-7.33 (5H, m), 9.57 (s, 1H).

步驟4 Step 4

在0℃下向化合物7-4(1.81g，6.13mmol)於DMF(18mL)中之攪拌溶液中添加二氟甲基三甲基矽烷(3.35mL，24.5mmol)及氟化銫(279mg，1.84mmol)。在室溫下攪拌4.5天之後，在0℃下將TBAF(THF中之1mol/L，6.13mL，6.13mmol)添加至混合物中。在0℃下攪拌所得混合物1h，且將水添加至混合物中。用乙酸乙酯萃取混合物。用鹽水洗滌經合併之有機層，經硫酸鈉乾燥且過濾。蒸發溶劑，且經由矽膠墊藉助於己烷及乙酸乙酯(1：1)過濾殘餘物。蒸發濾液，得到粗產物，其不經進一步純化即用於下一反應。 To a stirred solution of the compound 7-4 (1.81 g, 6.13 mmol) in DMF (18 mL) was added difluoromethyltrimethylnonane (3.35 mL, 24.5 mmol) and cesium fluoride (279 mg, 1.84). Mm). After stirring at room temperature for 4.5 days, TBAF (1 mol/L in THF, 6.13 mL, 6.13 mmol) was added to the mixture at 0 °C. The resulting mixture was stirred at 0 ° C for 1 h, and water was added to the mixture. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was evaporated and the residue was filtered with EtOAc EtOAc (EtOAc) The filtrate was evaporated to give a crude material which was applied to the next

在0℃下向粗產物於二氯甲烷(15mL)中之攪拌溶液中添加TFA(1.73mL，22.5mmol)。在室溫下攪拌2.5h之後，用碳酸氫鈉飽和溶液淬滅反應物。用二氯甲烷萃取混合物。經硫酸鈉乾燥經合併之有機層且過濾。蒸發溶劑，得到粗產物，其不經進一步純化即用於下一反應。 TFA (1.73 mL, 22.5 mmol) was added to a stirred solution of EtOAc. After stirring at room temperature for 2.5 h, the reaction was quenched with saturated sodium bicarbonate. The mixture was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and filtered. The solvent was evaporated to give a crude material.

在0℃下向粗產物於二氯甲烷(15mL)中之攪拌溶液中添加異硫氰酸苯甲醯酯(0.724mL，5.39mmol)。在室溫下攪拌100分鐘之後，蒸發溶劑。藉由急驟管柱層析(矽膠，3：1己烷：乙酸乙酯)純化粗產物，得到呈橙色非晶形形式之化合物7-5(749mg，41%)。以非對映異構體之混合物形式獲得此材料。MS：m/z=411.15[M+H]+。 To a stirred solution of the crude product in dichloromethane (15 mL), EtOAc (EtOAc) After stirring at room temperature for 100 minutes, the solvent was evaporated. The crude product was purified by flash column chromatography eluting elut elut elut elut elut This material is obtained as a mixture of diastereomers. MS: m/z = 411.15 [M + H] + .

步驟5 Step 5

在室溫下攪拌化合物7-5(749mg，1.83mmol)及WSCD．HCl(700mg，3.65mmol)於乙腈(7mL)中之懸浮液15h。添加水至反應混合物中，其隨後用乙酸乙酯萃取。用鹽水洗滌經合併之有機層，經硫酸鈉乾燥且過濾。蒸發溶劑，且藉由急驟管柱層析(矽膠，5：1至3：1至2：1己烷：乙酸乙酯之梯度)純化粗產物，得到呈黃色非晶形形式之化合物7-6(248mg，36%)。以非對映異構體之混合物形式獲得此材料。MS：m/z=377.15[M+H]+。 The compound 7-5 (749 mg, 1.83 mmol) and WSCD were stirred at room temperature. A suspension of HCl (700 mg, 3.65 mmol) in EtOAc (EtOAc) Water was added to the reaction mixture which was subsequently extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was evaporated, and the crude was purified by flash column chromatography eluting eluting eluting 248 mg, 36%). This material is obtained as a mixture of diastereomers. MS: m/z = 377.15 [M+H] + .

步驟6 Step 6

在室溫下攪拌化合物7-6(248mg，0.659mmol)、Boc2O(0.214mL，0.988mmol)及DMAP(16.1mg，0.132mmol)於THF(3mL)中之溶液3h。蒸發溶劑，且藉由急驟管柱層析(矽膠，91：9至84：16己烷：乙酸乙酯之梯度)純化粗產物，得到呈無色膠狀物狀之化合物7-7(140mg，45%)。 Was stirred at rt for compound 7-6 (248mg, 0.659mmol), was 3h Boc 2 O (0.214mL, 0.988mmol ) and DMAP (16.1mg, 0.132mmol) in THF (3mL) of. The solvent was evaporated, and the title compound was purified eluting elut elut elut elut elut elut elut elut elut elut elut elut %).

1H NMR(400MHz,CDCl3)1.19(d,J=7.0Hz,3H),1.41(s,9H),1.54(s,3H),2.67(q,J=7.0Hz,1H),4.00-4.05(m,1H),5.82(ddt,J=55.1,6.5,2.6Hz,1H),7.06(dd,J=12.5,7.9Hz,1H),7.14(t,J=7.6Hz),7.46(dd,J=15.4,7.9Hz,2H),7.56(t,J=7.6Hz,1H),7.77(d,J=8.2Hz,1H)。 1 H NMR (400 MHz, CDCl 3 ) 1.19 (d, J = 7.0 Hz, 3H), 1.41 (s, 9H), 1.54 (s, 3H), 2.67 (q, J = 7.0 Hz, 1H), 4.00-4.05 (m, 1H), 5.82 (ddt, J = 55.1, 6.5, 2.6 Hz, 1H), 7.06 (dd, J = 12.5, 7.9 Hz, 1H), 7.14 (t, J = 7.6 Hz), 7.46 (dd, J = 15.4, 7.9 Hz, 2H), 7.56 (t, J = 7.6 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H).

步驟7 Step 7

在室溫下攪拌化合物7-7(140mg，0.294mmol)及碳酸鉀(122mg，0.881mmol)於甲醇(2mL)中之懸浮液2h。添加水至反應混合物中，其隨後用乙酸乙酯萃取。用鹽水洗滌經合併之有機層，經硫酸鈉乾燥且過濾。蒸發溶劑，得到粗產物，其不經進一步純化即用於下一反應。 The suspension of compound 7-7 (140 mg, 0.294 mmol) and potassium carbonate (122 mg, 0.881 mmol) in methanol (2 mL) Water was added to the reaction mixture which was subsequently extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was evaporated to give a crude material.

在室溫下攪拌粗產物及TFA(0.226mL，2.93mmol)於二氯甲烷(2mL)中之溶液6.5h。用碳酸鉀飽和溶液淬滅反應物，其隨後用二氯甲 烷萃取。經硫酸鈉乾燥經合併之有機層且過濾。蒸發溶劑，得到粗產物，其不經進一步純化即用於下一反應。 The crude product and a solution of TFA (0.226 mL, 2.. The reaction was quenched with a saturated solution of potassium carbonate, which was subsequently treated with dichloromethane. Alkane extraction. The combined organic layers were dried over sodium sulfate and filtered. The solvent was evaporated to give a crude material.

在-25℃下向粗產物於TFA(1mL)中之攪拌溶液中添加硫酸(0.12mL，2.25mmol)，接著添加硝酸(0.020mL，0.441mmol)。在-25℃至-15℃下攪拌1.5h之後，用碳酸鉀飽和溶液淬滅反應物。用乙酸乙酯萃取混合物。用鹽水洗滌經合併之有機層，經硫酸鈉乾燥且過濾。蒸發溶劑，且藉由急驟管柱層析(胺基矽膠，2：1至1：1己烷：乙酸乙酯之梯度)純化粗產物，得到呈無色非晶形形式之化合物7-8(82.6mg，89%)。 Sulfuric acid (0.12 mL, 2.25 mmol) was added to a stirred solution of EtOAc (EtOAc) (EtOAc). After stirring at -25 ° C to -15 ° C for 1.5 h, the reaction was quenched with a saturated solution of potassium carbonate. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was evaporated and the crude was purified by flash chromatography eluting elut elut elut elut elut elut , 89%).

1H NMR(400MHz,CDCl3)1.14(d,J=7.0Hz,3H),1.54(s,3H),2.64(q,J=7.0Hz,1H),3.74-3.79(m,1H),5.76(ddt,J=55.3,6.3,1.9Hz,1H),7.21(t,J=9.9Hz,1H),8.16-8.20(m,1H),8.35(dd,J=6.8,2.6Hz,1H)。 1 H NMR (400MHz, CDCl 3 ) 1.14 (d, J = 7.0Hz, 3H), 1.54 (s, 3H), 2.64 (q, J = 7.0Hz, 1H), 3.74-3.79 (m, 1H), 5.76 (ddt, J = 55.3, 6.3, 1.9 Hz, 1H), 7.21 (t, J = 9.9 Hz, 1H), 8.16-8.20 (m, 1H), 8.35 (dd, J = 6.8, 2.6 Hz, 1H).

步驟8 Step 8

在60℃下攪拌化合物7-8(82.6mg，0.260mmol)、鐵粉(116mg，2.08mmol)及氯化銨(167mg，3.12mmol)於乙醇(0.8mL)、THF(0.4mL)及水(0.4mL)中之懸浮液100分鐘。將混合物冷卻至室溫，經由矽藻土(註冊商標)墊過濾。濾液用乙酸乙酯萃取。用鹽水洗滌經合併之有機層，經硫酸鈉乾燥且過濾。蒸發溶劑，得到粗產物(77.7mg)，其不經進一步純化即用於下一反應。 Compound 7-8 (82.6 mg, 0.260 mmol), iron powder (116 mg, 2.08 mmol) and ammonium chloride (167 mg, 3.12 mmol) in ethanol (0.8 mL), THF (0.4 mL) and water The suspension in 0.4 mL) was taken for 100 minutes. The mixture was cooled to room temperature and filtered through a pad of Celite (registered trademark). The filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was evaporated to give a crystal crystal crystal crystal crystal crystal.

在室溫下向粗產物(18.8mg)及鹽酸水溶液(2mol/L，0.033mL，0.065mmol)於甲醇(1mL)中之攪拌溶液中添加5-(氟甲氧基)吡-2-甲酸(12.4mg，0.072mmol)及WSCD．HCl(15.1mg，0.079mmol)。在室溫下攪拌1h之後，用氫氧化鈉水溶液淬滅反應物。用乙酸乙酯萃取混合物。用鹽水洗滌經合併之有機層，經硫酸鈉乾燥且過濾。蒸發溶劑，且藉由急驟管柱層析(胺基矽膠，1：1至0：1己烷：乙酸乙酯之梯度) 純化粗產物，得到呈灰白色固體之化合物I-33(25.0mg，87%)。 Add 5-(fluoromethoxy)pyridine to a stirred solution of the crude product (18.8 mg) and aqueous hydrochloric acid (2 mol/L, 0.033 mL, 0.065 mmol) in methanol (1 mL) 2-carboxylic acid (12.4 mg, 0.072 mmol) and WSCD. HCl (15.1 mg, 0.079 mmol). After stirring at room temperature for 1 h, the reaction was quenched with aqueous sodium hydroxide. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was evaporated, and the title compound was purified mjjjjjjjjjj %).

實例8 合成化合物I-34 Example 8 Synthesis of Compound I-34

步驟1 step 1

在0℃下向化合物8-1(4.59g，23.63mmol)於THF(45ml)中之溶 液中添加甲苯中之1.04mol/L DIBAL(56.8mL，59.1mmol)。在相同溫度下攪拌2h之後，用羅謝爾鹽飽和水溶液處理混合物且攪拌1.5h。用AcOEt萃取水層，且用鹽水洗滌合併之有機層。將有機層經MgSO4乾燥，過濾且濃縮。在0℃下將粗化合物溶解於CH2Cl2(30mL)中，且添加戴斯-馬丁高碘烷(11.94g，28.2mmol)。在室溫下攪拌2h之後，用NaHCO3飽和水溶液處理混合物且攪拌0.5h。用AcOEt萃取水層，且用鹽水洗滌合併之有機層，經MgSO4乾燥且過濾。在真空中濃縮濾液。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至40%溶離。蒸發收集之溶離份，獲得呈無色油狀之化合物8-2(3.67g，22.35mmol，95%)。 To a solution of the compound 8-1 (4.59 g, 23.63 mmol) in THF (45 ml), 1.04 mol/L DIBAL (56.8 mL, 59.1 mmol) in toluene was added at 0 °C. After stirring at the same temperature for 2 h, the mixture was treated with a saturated aqueous solution of Rochelle salt and stirred for 1.5 h. The aqueous layer was extracted with AcOEt and the combined organic layers were washed with brine. The organic layer was dried over MgSO 4, filtered and concentrated. At 0 ℃ The crude compound was dissolved in CH 2 Cl 2 (30mL), and the added Dess - Martin periodinane (11.94g, 28.2mmol). After stirring for 2h at room temperature, NaHCO 3 saturated aqueous solution and stirred with a mixture of 0.5h. The aqueous layer was extracted with AcOEt, and the combined organic layers and washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo. The crude product was added to a silica gel column and was eluted with hexanes/EtOAc from 0% to 40%. The collected fractions were evaporated to give compound 8-2 (3. <RTIgt;

1H-NMR(400MHz,CDCl3)δ：2.56(s,3H),6.22(d,J=8.0Hz,1H),7.11(dd,J=12.0,8.0Hz,1H),7.18(t,J=8.0Hz,1H),7.32(m,1H),7.37(m,1H),10.18(d,J=8.0Hz,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 2.56 (s, 3H), 6.22 (d, J = 8.0Hz, 1H), 7.11 (dd, J = 12.0,8.0Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.32 (m, 1H), 7.37 (m, 1H), 10.18 (d, J = 8.0 Hz, 1H).

步驟2 Step 2

在-10℃下向化合物8-2(2.01g，12.25mmol)及(三氟甲基)三甲基矽烷(2.61g，2.72mmol)於THF(30ml)中之溶液中添加THF(0.123ml，0.123mmol)中之1.00mol/L TBAF。在0℃下攪拌1h之後，向混合物添加THF中之1.00mol/L TBAF(1.23mL，1.23mmol)，且在室溫下攪拌混合物1h。用H2O稀釋反應混合物，且用AcOEt萃取水層。用H2O及鹽水洗滌合併之有機層，經MgSO4乾燥且過濾。在真空中濃縮濾液。 將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至30%溶離。蒸發收集之溶離份，獲得呈黃色油狀之化合物8-3(2.81g，12.00mmol，98%)。 To a solution of compound 8-2 (2.01 g, 12.25 mmol) and (trifluoromethyl)trimethylnonane (2.61 g, 2.72 mmol) in THF (30 mL) 1.00 mol/L TBAF in 0.123 mmol). After stirring at 0 ° C for 1 h, 1.00 mol/L TBAF (1.23 mL, 1.23 mmol) in THF was added to the mixture, and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with H 2 O with, and the aqueous layer was extracted with AcOEt. , 2 O and dried combined organic layers were washed with brine H over MgSO 4 and filtered. The filtrate was concentrated in vacuo. The crude product was added to a silica gel column and was eluted with hexane / EtOAc from 0% to 30%. The collected fractions were evaporated to give compound 8-3 (2.81 g, 12.00 mmol, 98%).

1H-NMR(400MHz,CDCl3)δ：2.19(d,J=8.0Hz,1H),2.20(s,3H),4.86(m,1H),5.67(d,J=8.0Hz,1H),7.06(dd,J=8.0,4.0Hz,1H),7.12(m,1H),7.25(m,1H),7.29(m,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 2.19 (d, J = 8.0Hz, 1H), 2.20 (s, 3H), 4.86 (m, 1H), 5.67 (d, J = 8.0Hz, 1H), 7.06 (dd, J = 8.0, 4.0 Hz, 1H), 7.12 (m, 1H), 7.25 (m, 1H), 7.29 (m, 1H).

步驟3 Step 3

在0℃下向化合物8-3(3.2g，13.66mmol)於CH2Cl2(40mL)中之溶液中添加m-CPBA(6.74g，27.3mmol)。在室溫下攪拌2h之後，用2mol/L NaOH(20.5mL)處理混合物且攪拌0.5h。用AcOEt萃取水層，且用鹽水洗滌合併之有機層，經MgSO4乾燥且過濾。在真空中濃縮濾液。粗產物不經進一步純化即用於下一反應。 m-CPBA (6.74 g, 27.3 mmol) was added to a solution of compound 8-3 (3.2 g, 13.66 mmol) in CH 2 Cl 2 (40 mL). After stirring at room temperature for 2 h, the mixture was treated with 2 mol/L NaOH (20.5 mL) and stirred for 0.5 h. The aqueous layer was extracted with AcOEt, and the combined organic layers and washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo. The crude product was used in the next reaction without further purification.

1H-NMR(400MHz,CDCl3)δ：1.72(s,3H),2.72(d,J=8.0Hz,1H),3.20(d,J=8.0Hz,1H),4.15(m,1H),7.05(m,1H),7.14(m,1H),7.31(m,1H),7.37(m,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.72 (s, 3H), 2.72 (d, J = 8.0Hz, 1H), 3.20 (d, J = 8.0Hz, 1H), 4.15 (m, 1H), 7.05 (m, 1H), 7.14 (m, 1H), 7.31 (m, 1H), 7.37 (m, 1H).

步驟4 Step 4

在室溫下向化合物8-4(3.42g，13.67mmol)及Ti(OEt)4(18.71g，82mmol)於DMF(30ml)中之溶液中添加NaN3(3.55mg，54.7mmol)。 在相同溫度下攪拌20h之後，用檸檬酸飽和水溶液處理混合物且攪拌1h。用AcOEt萃取水層，且用鹽水洗滌合併之有機層，經MgSO4乾燥且過濾。在真空中濃縮濾液。將粗產物添加至矽膠管柱中且用己烷/EtOAc 20%至60%溶離。蒸發收集之溶離份，獲得呈黃色固體狀之化合物8-5(3.03g，11.26mmol，82%)。 (, 82mmol 18.71g) in the in DMF (30ml) was added NaN 3 (3.55mg, 54.7mmol) to compound 8-4 (3.42g, 13.67mmol) and Ti (OEt) 4 at room temperature. After stirring at the same temperature for 20 h, the mixture was treated with saturated aqueous citric acid and stirred for 1 h. The aqueous layer was extracted with AcOEt, and the combined organic layers and washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo. The crude product was added to a silica gel column and was dissolved with hexane/EtOAc 20% to 60%. The collected fractions were evaporated to give compound 8-5 (3.03 g, 11.26 mmol, 82%).

1H-NMR(400MHz,CDCl3)δ：1.93(s,3H),2.85(d,J=8.0Hz,1H),3.19(d,J=4.0Hz,1H),3.75(m,1H),4.47(d,J=8.0Hz,1H),7.11(m,1H),7.22(m,1H),7.37(m,1H),7.58(m,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.93 (s, 3H), 2.85 (d, J = 8.0Hz, 1H), 3.19 (d, J = 4.0Hz, 1H), 3.75 (m, 1H), 4.47 (d, J = 8.0 Hz, 1H), 7.11 (m, 1H), 7.22 (m, 1H), 7.37 (m, 1H), 7.58 (m, 1H).

步驟5 Step 5

在室溫下向化合物8-5(3.03g，11.25mmol)於甲苯(30ml)及MeOH(30ml)中之溶液中添加氧化(二丁基)錫(3.36g，13.51mmol)。在110℃下攪拌3h之後，濃縮反應混合物。將無水甲苯(30ml)添加至殘餘物中，且蒸發混合物且在真空中乾燥。在室溫下將殘餘物溶解於甲苯(30ml)中，且添加四丁基溴化銨(0.726g，2.251mmol)及溴甲苯(3.34ml.28.1mmol)。在110℃下攪拌20h之後，用H2O稀釋反應混合 物且用AcOEt萃取。有機層經MgSO4乾燥，過濾且濃縮。將粗產物添加至矽膠管柱且用己烷/乙酸乙酯0%至30%溶離。蒸發收集之溶離份，獲得呈無色油狀之化合物8-6(3.1g，8.09mmol，72%)。 To a solution of compound 8-5 (3.03 g, 11.25 mmol) in toluene (30 ml) and MeOH (30 ml), EtOAc (3. After stirring at 110 ° C for 3 h, the reaction mixture was concentrated. Anhydrous toluene (30 ml) was added to the residue and the mixture was evaporated and dried in vacuo. The residue was dissolved in toluene (30 ml) at room temperature, and tetrabutylammonium bromide (0.726 g, 2.251 mmol) and bromotoluene (3.34 ml. 28.1 mmol) were added. After stirring at 110 ° C for 20 h, the reaction mixture was diluted with H 2 O and extracted with EtOAc. The organic layer was dried over MgSO 4, filtered and concentrated. The crude product was added to a silica gel column and was dissolved from 0% to 30% with hexane/ethyl acetate. The collected fractions were evaporated to give compound 8-6 (3.1 g, 8.09 <RTIgt;

1H-NMR(400MHz,CDCl3)δ：1.93(s,3H),3.29(d,J=12.0Hz,1H),3.47(q,J=8.0Hz,1H),4.43(d,J=8.0Hz,1H),4.75(m,2H),7.09(m,1H),7.20(m,1H),7.32-7.41(m,6H),7.56(m,1H)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.93 (s, 3H), 3.29 (d, J = 12.0 Hz, 1H), 3.47 (q, J = 8.0 Hz, 1H), 4.43 (d, J = 8.0) Hz, 1H), 4.75 (m, 2H), 7.09 (m, 1H), 7.20 (m, 1H), 7.32-7.41 (m, 6H), 7.56 (m, 1H).

步驟6 Step 6

在0℃下向NaH(939mg，23.48mmol)於THF(40mL)中之懸浮液中添加化合物8-6(3.0g，7.83mmol)。在室溫下攪拌30分鐘之後，向混合物中添加MeI(2.45mL，39.1mmol)，且在室溫下攪拌混合物30分鐘。用NH4Cl飽和水溶液處理反應混合物，且用AcOEt萃取水層。 用鹽水洗滌合併之有機層，經MgSO4乾燥且過濾。在真空中濃縮濾液。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至30%溶離。蒸發收集之溶離份，獲得呈無色油狀之化合物8-7(3.03g，7.63mmol，97%)。 Compound 8-6 (3.0 g, 7.83 mmol) was added to a suspension of NaH (939 mg, 23.48 mmol) in THF (40 mL). After stirring at room temperature for 30 minutes, MeI (2.45 mL, 39.1 mmol) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. With saturated NH 4 Cl aqueous solution the reaction mixture, and the aqueous layer was extracted with AcOEt. The combined organic layers were washed with brine, dried MgSO 4 and filtered. The filtrate was concentrated in vacuo. The crude product was added to a silica gel column and was eluted with hexane / EtOAc from 0% to 30%. The collected fractions were evaporated to give compound 8-7 (3.03 g, 7..

1H-NMR(400MHz,CDCl3)δ：1.91(s,3H),3.54(s,3H),3.61(s,1H),4.08(s,1H),4.72(s,2H),7.07(m,1H),7.15(m,1H),7.29-7.41(m,6H),7.51(m,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.91 (s, 3H), 3.54 (s, 3H), 3.61 (s, 1H), 4.08 (s, 1H), 4.72 (s, 2H), 7.07 (m , 1H), 7.15 (m, 1H), 7.29-7.41 (m, 6H), 7.51 (m, 1H).

步驟7 Step 7

在室溫下在氫氣氛圍下攪拌化合物8-7(3.0g，7.55mmol)及10%Pd/C(600mg)於MeOH(40ml)中之懸浮液。在相同溫度下攪拌24h之後，經由矽藻土(註冊商標)墊過濾混合物。於真空中濃縮濾液，得到呈白色固體狀之化合物8-8(2.13g，7.57mmol，100%)，其不經純化即用於下一步驟。 A suspension of compound 8-7 (3.0 g, 7.55 mmol) and 10% Pd/C (600 mg) in MeOH (40 mL) After stirring at the same temperature for 24 hours, the mixture was filtered through a pad of diatomaceous earth (registered trademark). The filtrate was concentrated in vacuo to give crystals crystals.

1H-NMR(400MHz,CDCl3)δ：1.65(s,3H),3.17(s,1H),3.61(s,3H),3.65(m,1H),3.99(s,1H),7.07(m,1H),7.20(m,1H),7.31(m,1H),7.56(m,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.65 (s, 3H), 3.17 (s, 1H), 3.61 (s, 3H), 3.65 (m, 1H), 3.99 (s, 1H), 7.07 (m , 1H), 7.20 (m, 1H), 7.31 (m, 1H), 7.56 (m, 1H).

步驟8 Step 8

在0℃下向化合物8-8(2.13g，7.57mmol)於CH2Cl2(30mL)中之攪拌溶液中添加異硫氰酸苯甲醯酯(1.22mL，6.82mmol)。在室溫下攪拌2h之後，濃縮反應混合物，且將所得殘餘物添加至矽膠管柱且用己烷/乙酸乙酯0%至50%溶離。蒸發收集之溶離份，獲得呈黃色非晶形形式之化合物8-9(3.03g，6.82mmol，90%) (, 7.57mmol 2.13g) was stirred in the in CH 2 Cl 2 (30mL) was added benzoyl isothiocyanate (1.22mL, 6.82mmol) of the compound 8-8 at 0 ℃. After stirring at room temperature for 2 h, the reaction mixture was concentrated, and the obtained residue was applied to a silica gel column and eluted from hexane/ethyl acetate 0% to 50%. The collected fractions were evaporated to give compound 8-9 (3.03 g, 6.82 mmol, 90%) as a yellow amorphous form.

1H-NMR(400MHz,CDCl3)δ：2.32(s,3H),3.48(s,1H),3.56(s,3H),3.95(m,1H),7.09(m,1H),7.18(m,1H),7.32(m,1H),7.41(m,1H),7.52(m,2H),7.63(m,1H),7.87(m,2H),8.88(m,1H),11.66(m,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 2.32 (s, 3H), 3.48 (s, 1H), 3.56 (s, 3H), 3.95 (m, 1H), 7.09 (m, 1H), 7.18 (m , 1H), 7.32 (m, 1H), 7.41 (m, 1H), 7.52 (m, 2H), 7.63 (m, 1H), 7.87 (m, 2H), 8.88 (m, 1H), 11.66 (m, 1H).

步驟9 Step 9

在室溫下向化合物8-9(3.03g，6.84mmol)於乙腈(30mL)中之攪拌溶液中添加EDC(3.93g，20.52mmol)。在相同溫度下攪拌20h之後，用H2O稀釋反應混合物且用乙酸乙酯萃取。合併有機層且用鹽水洗滌。將有機層經MgSO4乾燥，過濾且濃縮。粗產物不經進一步純化即用於下一反應。 EDC (3.93 g, 20.52 mmol) was added to a stirred solution of Compound 8-9 (3.03 g, 6.84 mmol) in EtOAc (30 mL). After stirring at the same temperature for 20 h, the reaction mixture was diluted with H 2 o and evaporated. The organic layers were combined and washed with brine. The organic layer was dried over MgSO 4, filtered and concentrated. The crude product was used in the next reaction without further purification.

1H-NMR(400MHz,CDCl3)δ：1.87(s,3H),3.71(s,3H),4.23(s,1H),4.31(m,1H),7.15(m,1H),7.23(m,1H),7.35-7.55(m,5H),8.28(m,2H),11.64(m,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.87 (s, 3H), 3.71 (s, 3H), 4.23 (s, 1H), 4.31 (m, 1H), 7.15 (m, 1H), 7.23 (m , 1H), 7.35-7.55 (m, 5H), 8.28 (m, 2H), 11.64 (m, 1H).

步驟10 Step 10

在室溫下在氮氣下向化合物8-10(2.81g，6.85mmol)於THF(40mL)中之攪拌溶液中添加Boc2O(2.385mL，10.27mmol)及DMAP(251mg，2.05mmol)。在攪拌1h之後，用H2O稀釋反應混合物且用乙酸乙酯萃取。合併有機層且用鹽水洗滌。將有機層經MgSO4乾燥，過濾且濃縮。在0℃下將粗化合物溶解於甲醇(40mL)中，且添加K2CO3(2.50g，18.1mmol)。在室溫下攪拌2h之後，用H2O稀釋反應混合物且用乙酸乙酯萃取。將有機層經MgSO4乾燥，過濾且濃縮。將粗產物添加 至矽膠管柱且用己烷/乙酸乙酯0%至30%溶離。蒸發收集之溶離份，獲得經Boc保護之化合物。在0℃下將化合物溶解於CH2Cl2(15mL)中，且添加TFA(4ml)。在室溫下攪拌2h之後，用20%Na2CO3水溶液淬滅反應混合物且用乙酸乙酯萃取。將有機層經MgSO4乾燥且過濾。 於真空中濃縮濾液，得到呈白色非晶形形式之化合物8-11(1.16g，3.79mmol，55%)，其不經純化即用於下一步驟。 Was added at room temperature under nitrogen a solution of compound 8-10 (2.81g, 6.85mmol) in THF (40mL) was stirred in a solution of Boc 2 O (2.385mL, 10.27mmol) and DMAP (251mg, 2.05mmol). After stirring for 1h, the reaction mixture was diluted with H 2 O and extracted with ethyl acetate. The organic layers were combined and washed with brine. The organic layer was dried over MgSO 4, filtered and concentrated. At 0 ℃ The crude compound was dissolved in methanol (40 mL), and the added K 2 CO 3 (2.50g, 18.1mmol ). After stirring for 2h at room temperature the reaction mixture was diluted with H 2 O and extracted with ethyl acetate. The organic layer was dried over MgSO 4, filtered and concentrated. The crude product was added to a silica gel column and was dissolved from 0% to 30% with hexane/ethyl acetate. The collected fractions were evaporated to give a Boc-protected compound. At 0 ℃ The compound was dissolved in CH 2 Cl 2 (15mL), and was added TFA (4ml). After stirring for 2h at room temperature, 20% Na 2 CO 3 aqueous reaction mixture was quenched and extracted with ethyl acetate. The organic layer was dried and filtered over MgSO 4. The filtrate was concentrated in vacuo to give crystals crystals crystals crystals crystals

1H-NMR(400MHz,CDCl3)δ：1.69(s,3H),3.66(s,3H),3.99(m,1H),4.16(s,1H),7.07(dd,J=12.0.8.0Hz,1H),7.17(t,J=8.0Hz,1H),7.30(m,1H),7.39(t,J=8.0Hz,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.69 (s, 3H), 3.66 (s, 3H), 3.99 (m, 1H), 4.16 (s, 1H), 7.07 (dd, J = 12.0.8.0Hz , 1H), 7.17 (t, J = 8.0 Hz, 1H), 7.30 (m, 1H), 7.39 (t, J = 8.0 Hz, 1H).

步驟11 Step 11

在-10℃下向化合物8-11(1.14g，3.72mmol)於TFA(4.9ml)中之溶液中添加硫酸(1.25ml，23.5mmol)。在-10℃下攪拌5分鐘之後，在-10℃下向反應混合物中添加HNO3(0.36ml，5.58mmol)。在-10℃下攪拌30分鐘之後，用K2CO3水溶液處理反應混合物。用AcOEt萃取水層，且經MgSO4乾燥有機層，過濾且濃縮。於真空中濃縮濾液，得到呈白色非晶形形式之化合物8-12(1.23g，3.50mmol，94%)。 Sulfuric acid (1.25 ml, 23.5 mmol) was added to a solution of compound 8-11 (1.14 g, 3.72 mmol) in EtOAc. After stirring at -10 ℃. 5 minutes, at -10 ℃ the reaction mixture HNO 3 (0.36ml, 5.58mmol). After stirring at -10 ° C for 30 minutes, the reaction mixture was treated with aqueous K 2 CO 3 . The aqueous layer was extracted with AcOEt, and organic layer was dried and MgSO 4, filtered and concentrated. The filtrate was concentrated in vacuo to afford compound 8-12 (1.23 g, 3.

1H-NMR(400MHz,CDCl3)δ：1.67(s,3H),3.67(s,3H),3.93(m,1H),4.13(m,1H),7.07(m,1H),8.21(m,1H),8.39(m,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.67 (s, 3H), 3.67 (s, 3H), 3.93 (m, 1H), 4.13 (m, 1H), 7.07 (m, 1H), 8.21 (m , 1H), 8.39 (m, 1H).

步驟12 Step 12

在室溫下向化合物8-12(1.2g，3.42mmol)及DMAP(125mg，1.027mmol)於THF(10ml)中之溶液中添加Boc2O(2.38ml，10.3mmol)。在相同溫度下攪拌2h之後，在真空下濃縮混合物。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至30%溶離。蒸發收集之溶離份，獲得呈白色非晶形形式之化合物8-13(1.73g，3.14mmol，92%)。 Add Boc 2 O (2.38ml, 10.3mmol) (10ml) in the solution at a solution of compound 8-12 (1.2g, 3.42mmol) and DMAP (125mg, 1.027mmol) in THF. After stirring at the same temperature for 2 h, the mixture was concentrated under vacuum. The crude product was added to a silica gel column and was eluted with hexane / EtOAc from 0% to 30%. The collected fractions were evaporated to give compound 8-13 (1.73 g, 3..

1H-NMR(400MHz,CDCl3)δ：1.53(s,18H),1.57(s,3H),3.64(s, 3H),4.02(m,1H),4.15(s,1H),7.27(m,1H),8.25(m,1H),8.50(m,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.53 (s, 18H), 1.57 (s, 3H), 3.64 (s, 3H), 4.02 (m, 1H), 4.15 (s, 1H), 7.27 (m , 1H), 8.25 (m, 1H), 8.50 (m, 1H).

步驟13 Step 13

在室溫下在氫氣氛圍下攪拌化合物8-13(1.73g，3.14mmol)、10%Pd/C(300mg)於MeOH(8ml)及THF(6ml)中之懸浮液。在相同溫度下攪拌2h之後，經由矽藻土(註冊商標)墊過濾混合物。於真空中濃縮濾液，得到呈白色非晶形形式之化合物8-14(1.63g，3.13mmol，99%)，其不經純化即用於下一步驟。 A suspension of compound 8-13 (1.73 g, 3.14 mmol), 10% Pd/C (300 mg) in MeOH (8 mL) and THF (6 ml) was stirred at room temperature. After stirring at the same temperature for 2 h, the mixture was filtered through a pad of diatomaceous earth (registered trademark). The filtrate was concentrated in vacuo to give crystals crystals crystals crystals crystals

1H-NMR(400MHz,CDCl3)δ：1.52(s,18H),1.57(s,3H),3.59(s,3H),4.13(m,1H),4.14(m,1H),6.55(m,1H),6.83(m,1H),6.87(m,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.52 (s, 18H), 1.57 (s, 3H), 3.59 (s, 3H), 4.13 (m, 1H), 4.14 (m, 1H), 6.55 (m , 1H), 6.83 (m, 1H), 6.87 (m, 1H).

步驟14 Step 14

在室溫下向化合物8-14(201mg，0.385mmol)於CH2Cl2(2ml)中之溶液中添加5-氰基吡啶甲酸水合物(70.4mg，0.424mmol)、HATU(161mg，0.424mmol)及DIPEA(0.101ml，0.578mmol)。在相同溫度下攪拌18h之後，用H2O處理反應混合物。用AcOEt萃取水層，且經MgSO4乾燥有機層，過濾且濃縮。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至50%溶離。蒸發收集之溶離份，獲得呈白色非晶形形式之化合物8-15(245mg，0.376mmol，98%)。 Was added 5-cyano-pyridine-carboxylic acid hydrate (70.4mg, 0.424mmol) of the compound in 8-14 (201mg, 0.385mmol) in CH 2 Cl 2 (2ml) at room temperature was, HATU (161mg, 0.424mmol ) and DIPEA (0.101 ml, 0.578 mmol). After stirring at the same temperature for 18 h, the reaction mixture was treated with H 2 O. The aqueous layer was extracted with AcOEt, and organic layer was dried and MgSO 4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with hexanes/EtOAc from 0% to 50%. The collected fractions were evaporated to give compound 8-15 (245 mg, 0.376 mmol, 98%).

1H-NMR(400MHz,CDCl3)δ：1.56(s,18H),1.75(s,3H),3.63(s,3H),4.11(m,1H),4.16(m,1H),7.16(dd,J=12.0.8.0Hz,1H),7.55(dd,J=8.0,4.0Hz,1H),8.22(dd,J=8.0,4.0Hz,1H),8.39(m,1H),8.43(d,J=8.0Hz,1H),8.79(m,1H),9.98(s,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.56 (s, 18H), 1.75 (s, 3H), 3.63 (s, 3H), 4.11 (m, 1H), 4.16 (m, 1H), 7.16 (dd , J=12.0.8.0 Hz, 1H), 7.55 (dd, J=8.0, 4.0 Hz, 1H), 8.22 (dd, J=8.0, 4.0 Hz, 1H), 8.39 (m, 1H), 8.43 (d, J = 8.0 Hz, 1H), 8.79 (m, 1H), 9.98 (s, 1H).

步驟15 Step 15

在0℃下向化合物8-15(44mg，0.073mmol)於CH2Cl2(1.5ml)中之溶液中添加TFA(0.5ml)。在室溫下攪拌2h之後，用20%K2CO3水溶液淬滅反應混合物。用AcOEt萃取水層且合併有機層且用鹽水洗滌。將有機層經MgSO4乾燥，過濾且濃縮。藉由超臨界流體層析 (SFC)(Chiralpak(註冊商標)IB；具有0.1%二乙胺之5%-40%乙醇)純化粗產物，得到呈白色固體狀之化合物I-34(58mg，0.128mmol，34%)。 Added at 0 ℃ solution of compound 8-15 (44mg, 0.073mmol) in the solution in CH 2 Cl 2 (1.5ml) in TFA (0.5ml). After stirring for 2h at room temperature with 2 CO 3 20% K aqueous reaction mixture was quenched. The aqueous layer was extracted with AcOEt and organic layers were combined and washed with brine. The organic layer was dried over MgSO 4, filtered and concentrated. The crude product was purified by supercritical fluid chromatography (SFC) (Chiralpak (registered trademark) IB; 5% to 40% ethanol with 0.1% diethylamine) to give compound I-34 (58 mg, 0.128) as a white solid. M, 34%).

實例9 合成化合物I-35 Example 9 Synthesis of Compound I-35

步驟1 step 1

在室溫下向鋅(1.20g，18.27mmol)於THF(10ml)中之懸浮液中添加溴二氟乙酸乙酯(5.19g，25.6mmol)於THF(10ml)中之溶液及化合物9-1(1.2g，7.31mmol)於THF(10ml)中之溶液。在相同溫度下攪拌2h之後，用NH4Cl飽和水溶液處理反應混合物，且用AcOEt萃取水層。用鹽水洗滌合併之有機層，經Na2SO4乾燥，過濾且濃縮。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至40%溶離。蒸發收集之溶離份，獲得呈無色油狀之化合物9-2(1.91g，6.63mmol，91%)。 To a suspension of zinc (1.20 g, 18.27 mmol) in THF (10 mL) (1.2 g, 7.31 mmol) in THF (10 mL). After stirring for 2h at the same temperature, aqueous saturated NH 4 Cl by treatment of the reaction mixture, and the aqueous layer was extracted with AcOEt. , Dried combined organic layers were washed with brine, Na 2 SO 4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with hexanes/EtOAc from 0% to 40%. The collected fractions were evaporated to give compound 9-2 (1.91 g, 6..

1H-NMR(400MHz,CDCl3)δ：1.37(t,J=8.0Hz,3H)2.15(s,3H),2.21(d,J=4.0Hz,1H),4.38(q,J=8.0Hz,2H),4.98(m,1H),5.67(d,J=8.0Hz,1H),7.04(m,1H),7.11(t,J=8.0Hz,1H),7.24(m,1H),7.28(m,1H)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.37 (t, J = 8.0 Hz, 3H) 2.15 (s, 3H), 2.21. (d, J = 4.0 Hz, 1H), 4.38 (q, J = 8.0 Hz) , 2H), 4.98 (m, 1H), 5.67 (d, J = 8.0 Hz, 1H), 7.04 (m, 1H), 7.11 (t, J = 8.0 Hz, 1H), 7.24 (m, 1H), 7.28 (m, 1H).

步驟2 Step 2

在0℃下向化合物9-2(2.09g，7.24mmol)於MeOH(80ml)中之溶液中添加NaBH4(822mg，21.7mmol)。在相同溫度下攪拌0.5h之後，用NH4Cl飽和水溶液處理混合物且攪拌0.5h。用AcOEt萃取水層，且用鹽水洗滌合併之有機層。將有機層經MgSO4乾燥，過濾且濃縮。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至40%溶離。蒸發收集之溶離份，獲得呈無色油狀之化合物9-3(1.70g，6.91mmol，95%)。 Was added a solution of compound 9-2 (2.09g, 7.24mmol) in MeOH (80ml) in a solution of NaBH 4 (822mg, 21.7mmol) at 0 ℃. After stirring for 0.5h at the same temperature, with saturated NH 4 Cl aqueous solution and the mixture was stirred for 0.5h. The aqueous layer was extracted with AcOEt and the combined organic layers were washed with brine. The organic layer was dried over MgSO 4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with hexanes/EtOAc from 0% to 40%. The collected fractions were evaporated to give compound 9-3 (1.70 g, 6.

1H-NMR(400MHz,CDCl3)δ：2.14(s,3H),2.32(t,J=8.0Hz,1H),2.39(d,J=8.0Hz,1H),3.92(m,1H),4.02(m,1H),4.88(m,1H),5.72(d,J=12.0Hz,1H),7.04(m,1H),7.10(t,J=8.0Hz,1H),7.25(m,1H),7.27(m,1H)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 2.14 (s, 3H), 2.32 (t, J = 8.0 Hz, 1H), 2.39 (d, J = 8.0 Hz, 1H), 3.92 (m, 1H), 4.02 (m, 1H), 4.88 (m, 1H), 5.72 (d, J = 12.0 Hz, 1H), 7.04 (m, 1H), 7.10 (t, J = 8.0 Hz, 1H), 7.25 (m, 1H) ), 7.27 (m, 1H).

步驟3 Step 3

在室溫下向化合物9-3(1.71g，6.94mmol)於CH2Cl2(30ml)中之 溶液中添加TBSCl(2.09g，13.89mmol)及咪唑(0.946g，13.89mmol)。在相同溫度下攪拌0.5h之後，用水處理混合物且攪拌0.5h。 用AcOEt萃取水層，且用鹽水洗滌合併之有機層。將有機層經MgSO4乾燥，過濾且濃縮。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至20%溶離。蒸發收集之溶離份，獲得呈無色油狀之化合物9-4(1.95g，5.42mmol，78%)。 TBSCl (2.09 g, 13.89 mmol) and imidazole (0.946 g, 13.89 mmol) were added to a solution of compound 9-3 (1.71 g, 6.94 mmol) in CH 2 Cl 2 (30 mL). After stirring at the same temperature for 0.5 h, the mixture was treated with water and stirred for 0.5 h. The aqueous layer was extracted with AcOEt and the combined organic layers were washed with brine. The organic layer was dried over MgSO 4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with hexanes/EtOAc from 0% to 20%. The collected fractions were evaporated to give compound 9-4 (1.95 g, 5.42 mmol, 78%).

1H-NMR(400MHz,CDCl3)δ：0.10(s,3H),0.12(s,3H),0.92(s,9H),2.13(s,3H),2.31(d,J=4.0Hz,1H),3.87(m,1H),3.99(m,1H),4.88(m,1H),5.70(d,J=12.0Hz,1H),7.04(dd,J=12.0,8.0Hz,1H),7.10(t,J=8.0Hz,1H),7.24(m,1H),7.26(m,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 0.10 (s, 3H), 0.12 (s, 3H), 0.92 (s, 9H), 2.13 (s, 3H), 2.31 (d, J = 4.0Hz, 1H ), 3.87 (m, 1H), 3.99 (m, 1H), 4.88 (m, 1H), 5.70 (d, J = 12.0 Hz, 1H), 7.04 (dd, J = 12.0, 8.0 Hz, 1H), 7.10 (t, J = 8.0 Hz, 1H), 7.24 (m, 1H), 7.26 (m, 1H).

步驟4 Step 4

在0℃下向化合物9-4(1.95g，5.42mmol)於CH2Cl2(30ml)中之溶液中添加m-CPBA(2.67g，10.8mmol)。在室溫下攪拌2h之後，用2mol/L NaOH(20.5mL)處理混合物且攪拌0.5h。用AcOEt萃取水層，且用鹽水洗滌合併之有機層，經MgSO4乾燥且過濾。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至30%溶離。蒸發收集之溶離份，獲得呈無色油狀之化合物9-5(1.92g，5.10mmol，94%)。 Added at 0 ℃ solution of compound 9-4 (1.95g, 5.42mmol) in CH of the 2 Cl 2 (30ml) solution of m-CPBA (2.67g, 10.8mmol) . After stirring at room temperature for 2 h, the mixture was treated with 2 mol/L NaOH (20.5 mL) and stirred for 0.5 h. The aqueous layer was extracted with AcOEt, and the combined organic layers and washed with brine, dried over MgSO 4 and filtered. The crude product was added to a silica gel column and was eluted with hexane / EtOAc from 0% to 30%. The collected fractions were evaporated to give compound 9-5 (1.92 g, 5.10 mmol, 94%).

1H-NMR(400MHz,CDCl3)δ：0.11(s,6H),0.90(s,9H),1.71(s,3H),2.61(d,J=8.0Hz,1H),3.28(d,J=8.0Hz,1H),3.94(m,1H),4.03(m,1H),4.10(m,1H),7.03(m,1H),7.12(t,J=8.0Hz,1H),7.27(m,1H),7.38(m,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 0.11 (s, 6H), 0.90 (s, 9H), 1.71 (s, 3H), 2.61 (d, J = 8.0Hz, 1H), 3.28 (d, J = 8.0 Hz, 1H), 3.94 (m, 1H), 4.03 (m, 1H), 4.10 (m, 1H), 7.03 (m, 1H), 7.12 (t, J = 8.0 Hz, 1H), 7.27 (m) , 1H), 7.38 (m, 1H).

步驟5 Step 5

在0℃下向化合物9-5(1.92g，5.10mmol)於THF(25ml)中之溶液中添加THF(5.61ml，5.61mmol)中之1.00mol/L TBAF。在相同溫度下攪拌2h之後，用NaHCO3飽和水溶液處理混合物且攪拌0.5h。用AcOEt萃取水層，且用鹽水洗滌合併之有機層。將有機層經MgSO4乾 燥，過濾且濃縮。將粗產物添加至矽膠管柱且用己烷/EtOAc 10%至50%溶離。蒸發收集之溶離份，獲得呈無色油狀之化合物9-6(1.31g，5.00mmol，98%)。 1.00 mol/L TBAF in THF (5.61 ml, 5.61 mmol) was added to a solution of compound 9-5 (1.92 g, 5.10 mmol) in THF (25 ml). After stirring for 2h at the same temperature, NaHCO 3 saturated aqueous solution and stirred with a mixture of 0.5h. The aqueous layer was extracted with AcOEt and the combined organic layers were washed with brine. The organic layer was dried over MgSO 4, filtered and concentrated. The crude product was added to a silica gel column and was dissolved with hexanes/EtOAc 10% to 50%. The collected fractions were evaporated to give compound 9-6 (1.31 g, 5.00 mmol, 98%).

1H-NMR(400MHz,CDCl3)δ：1.72(s,3H),2.09(t,J=4.0Hz,1H)2.63(d,J=4.0Hz,1H),3.31(d,J=8.0Hz,1H),3.97-4.18(m,3H),7.05(m,1H),7.13(t,J=8.0Hz,1H),7.29(m,1H),7.39(t,J=8.0Hz,1H)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.72 (s, 3H), 2.09 (t, J = 4.0 Hz, 1H) 2.63 (d, J = 4.0 Hz, 1H), 3.31 (d, J = 8.0 Hz) , 1H), 3.97-4.18 (m, 3H), 7.05 (m, 1H), 7.13 (t, J = 8.0 Hz, 1H), 7.29 (m, 1H), 7.39 (t, J = 8.0 Hz, 1H) .

步驟6 Step 6

在室溫下向9-6(1.31g，5.00mmol)及Ti(OEt)4(6.85g，30.0mmol)於DMF(12ml)中之溶液中添加NaN3(1.30g，20.0mmol)。在相同溫度下攪拌20h之後，用檸檬酸飽和水溶液處理混合物且攪拌1h。 用AcOEt萃取水層，且用鹽水洗滌合併之有機層，經MgSO4乾燥且過濾。在真空中濃縮濾液。將粗產物添加至矽膠管柱中且用己烷/EtOAc 20%至60%溶離。蒸發收集之溶離份，獲得呈白色固體狀之化合物9-7(1.38g，4.52mmol，90%)。 NaN 3 (1.30 g, 20.0 mmol) was added to a solution of 9-6 (1.31 g, 5.00 mmol) and Ti(OEt) 4 (6.85 g, 30.0 mmol) in DMF (12 ml). After stirring at the same temperature for 20 h, the mixture was treated with saturated aqueous citric acid and stirred for 1 h. The aqueous layer was extracted with AcOEt, and the combined organic layers and washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo. The crude product was added to a silica gel column and was dissolved with hexane/EtOAc 20% to 60%. The collected fractions were evaporated to give compound 9-7 (1.38 g, 4.52 mmol,

1H-NMR(400MHz,CDCl3)δ：1.93(s,3H),2.70(br,1H),3.22(d,J=8.0Hz,1H),3.38(br,1H),3.67(m,1H),3.77(m,1H),3.90(m,1H),4.50(s,1H),7.10(dd,J=12.0,8.0Hz,1H),7.20(t,J=8.0Hz,1H),7.35(m,1H),7.58(t,J=8.0Hz,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.93 (s, 3H), 2.70 (br, 1H), 3.22 (d, J = 8.0Hz, 1H), 3.38 (br, 1H), 3.67 (m, 1H ), 3.77 (m, 1H), 3.90 (m, 1H), 4.50 (s, 1H), 7.10 (dd, J = 12.0, 8.0 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 7.35 (m, 1H), 7.58 (t, J = 8.0 Hz, 1H).

步驟7 Step 7

在0℃下向化合物9-7(1.38g，4.52mmol)及對甲苯磺醯氯(0.95g，4.97mmol)於CH2Cl2(26ml)中之溶液中添加DMAP(1.11g，9.04mmol)。在相同溫度下攪拌2h之後，用NaHCO3飽和水溶液處理混合物且攪拌0.5h。用AcOEt萃取水層，且用0.1mol/L HCl水溶液及鹽水洗滌合併之有機層，經MgSO4乾燥且過濾。在真空中濃縮濾液。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至30%溶離。蒸發收集之 溶離份，獲得呈無色油狀之化合物9-8(1.92g，4.18mmol，92%)。 DMAP was added a solution of compound 9-7 (1.38g, 4.52mmol) and p-toluene sulfonic acyl chloride (0.95g, 4.97mmol) in CH 2 Cl 2 (26ml) in the solution at 0 ℃ (1.11g, 9.04mmol) . After stirring for 2h at the same temperature, NaHCO 3 saturated aqueous solution and stirred with a mixture of 0.5h. The aqueous layer and treated with an aqueous solution of 0.1mol L HCl and the organic layer / the combined extracts washed with brine and AcOEt,, dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo. The crude product was added to a silica gel column and was eluted with hexane / EtOAc from 0% to 30%. The collected fractions were evaporated to give compound 9-8 (1.92 g, 4.

1H-NMR(400MHz,CDCl3)δ：1.90(s,3H),2.46(s,3H),2.83(d,J=8.0Hz,1H),3.05(d,J=8.0Hz,1H),3.61(s,1H),4.20(m,1H),4.28(m,1H),4.42(d,J=8.0Hz,1H),7.08(dd,J=12.0,8.0Hz,1H),7.20(t,J=8.0Hz,1H),7.34(m,4H),7.54(m,1H),7.72(m,2H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.90 (s, 3H), 2.46 (s, 3H), 2.83 (d, J = 8.0Hz, 1H), 3.05 (d, J = 8.0Hz, 1H), 3.61(s,1H), 4.20(m,1H), 4.28(m,1H), 4.42(d,J=8.0Hz,1H),7.08(dd,J=12.0,8.0Hz,1H), 7.20(t , J = 8.0 Hz, 1H), 7.34 (m, 4H), 7.54 (m, 1H), 7.72 (m, 2H).

步驟8 Step 8

在室溫下向化合物9-8(1.92g，4.18mmol)於MeOH(30ml)中之溶液中添加K2CO3(1.16g，8.36mmol)。在相同溫度下攪拌20h之後，用水處理混合物且攪拌0.5h。用AcOEt萃取水層，且用鹽水洗滌合併之有機層，經MgSO4乾燥且過濾。在真空中濃縮濾液。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至30%溶離。蒸發收集之溶離份，獲得呈無色油狀之化合物9-9(1.10g，3.84mmol，92%)。 Add K 2 CO 3 (1.16g, 8.36mmol ) in the direction (1.92g, 4.18mmol) in MeOH (30ml) solution of the compound 9-8 at room temperature. After stirring at the same temperature for 20 h, the mixture was treated with water and stirred for 0.5 h. The aqueous layer was extracted with AcOEt, and the combined organic layers and washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo. The crude product was added to a silica gel column and was eluted with hexane / EtOAc from 0% to 30%. The collected fractions were evaporated to give compound 9-9 (1.10 g, 3.84 mmol, 92%).

1H-NMR(400MHz,CDCl3)δ：1.92(s,3H),3.72(m,1H),3.78(m,1H),4.04(m,1H),4.28(m,1H),4.74(m,1H),7.09(dd,J=12.0,8.0Hz,1H),7.19(t,J=8.0Hz,1H),7.33(m,1H),7.67(m,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.92 (s, 3H), 3.72 (m, 1H), 3.78 (m, 1H), 4.04 (m, 1H), 4.28 (m, 1H), 4.74 (m , 1H), 7.09 (dd, J = 12.0, 8.0 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 7.33 (m, 1H), 7.67 (m, 1H).

步驟9 Step 9

在室溫下在氫氣氛圍下攪拌化合物9-9(1.05g，3.66mmol)於MeOH(25ml)及10%Pd/C(200mg)中之懸浮液。在相同溫度下攪拌24h之後，經由矽藻土(註冊商標)墊過濾混合物。於真空中濃縮濾液，得到呈白色固體狀之化合物9-10(0.9g，3.47mmol，95%)，其不經純化即用於下一步驟。 A suspension of compound 9-9 (1.05 g, 3.66 mmol) in MeOH (25 mL) and 10% Pd / C (200 mg) was stirred at room temperature. After stirring at the same temperature for 24 hours, the mixture was filtered through a pad of diatomaceous earth (registered trademark). The filtrate was concentrated in vacuo to give a crystallite.

1H-NMR(400MHz,CDCl3)δ：1.70(s,3H),3.67(dd,J=8.0,4.0Hz,1H),4.04(m,1H),4.25(m,1H),4.54(m,1H),7.09(dd,J=12.0,8.0Hz,1H),7.20(t,J=8.0Hz,1H),7.33(m,1H),7.55(m,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.70 (s, 3H), 3.67 (dd, J = 8.0,4.0Hz, 1H), 4.04 (m, 1H), 4.25 (m, 1H), 4.54 (m , 1H), 7.09 (dd, J = 12.0, 8.0 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 7.33 (m, 1H), 7.55 (m, 1H).

步驟10 Step 10

在0℃下向化合物9-10(750mg，2.87mmol)於CH2Cl2(15mL)中 之攪拌溶液中添加異硫氰酸苯甲醯酯(0.579mL，4.31mmol)。在室溫下攪拌6h之後，濃縮反應混合物，且將所得殘餘物添加至矽膠管柱且用己烷/乙酸乙酯0%至35%溶離。蒸發收集之溶離份，獲得呈無色非晶形形式之化合物9-11(1.07g，2.51mmol，87%)。 Benzoyl isothiocyanate was added a solution of compound 9-10 (750mg, 2.87mmol) in CH 2 Cl 2 (15mL) was stirred in the solution at 0 ℃ (0.579mL, 4.31mmol). After stirring at room temperature for 6 h, the reaction mixture was concentrated, and the obtained residue was applied to a hexane column and eluted from hexane/ethyl acetate 0% to 35%. The collected fractions were evaporated to give compound 9-11 (1.07 g, 2.51 mmol, 87%).

1H-NMR(400MHz,CDCl3)δ：2.28(s,3H),3.96(m,1H),4.14(m,1H),4.46(m,1H),4.80(m,1H),7.06(dd,J=12.0,8.0Hz,1H),7.14(t,J=8.0Hz,1H),7.29(m,1H),7.52(m,3H),7.62(t,J=8.0Hz,1H),7.87(d,J=4.0Hz,1H),8.86(s,1H),11.81(s,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 2.28 (s, 3H), 3.96 (m, 1H), 4.14 (m, 1H), 4.46 (m, 1H), 4.80 (m, 1H), 7.06 (dd , J = 12.0, 8.0 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 7.29 (m, 1H), 7.52 (m, 3H), 7.62 (t, J = 8.0 Hz, 1H), 7.87 (d, J = 4.0 Hz, 1H), 8.86 (s, 1H), 11.81 (s, 1H).

步驟11 Step 11

在室溫下向化合物9-11(1.156g，2.72mmol)於乙腈(15mL)中之攪拌溶液中添加EDC(1.04g，5.45mmol)。在相同溫度下攪拌20h之後，用H2O稀釋反應混合物且用乙酸乙酯萃取。合併有機層且用鹽水洗滌。將有機層經MgSO4乾燥，過濾且濃縮。將粗產物添加至矽膠管柱且用己烷/乙酸乙酯0%至40%溶離。蒸發收集之溶離份，獲得呈白色固體狀之化合物9-12(853mg，2.19mmol，80%)。 EDC (1.04 g, 5.45 mmol) was added to a stirred solution of compound 9-11 (1. <RTI ID=0.0></RTI></RTI><RTIgt; After stirring at the same temperature for 20 h, the reaction mixture was diluted with H 2 o and evaporated. The organic layers were combined and washed with brine. The organic layer was dried over MgSO 4, filtered and concentrated. The crude product was added to a silica gel column and was dissolved from 0% to 40% with hexane/ethyl acetate. The collected fractions were evaporated to give compound 9-12 ( </RTI><RTIgt;

1H-NMR(400MHz,CDCl3)δ：1.86(s,3H),4.13-4.33(m,3H),4.87(s,1H),7.15(m,1H),7.18(m,1H),7.30(m,1H),7.38(m,1H),7.44(t,J=8.0Hz,2H),7.53(t,J=8.0Hz,1H),8.28(d,J=8.0Hz,2H),11.62(s,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.86 (s, 3H), 4.13-4.33 (m, 3H), 4.87 (s, 1H), 7.15 (m, 1H), 7.18 (m, 1H), 7.30 (m, 1H), 7.38 (m, 1H), 7.44 (t, J = 8.0 Hz, 2H), 7.53 (t, J = 8.0 Hz, 1H), 8.28 (d, J = 8.0 Hz, 2H), 11.62 (s, 1H).

步驟12 Step 12

在室溫下向化合物9-12(853mg，2.19mmol)於THF(10mL)中之攪拌溶液中添加Boc2O(0.761mL，3.28mmol)及DMAP(80mg，0.656mmol)。在攪拌1h之後，用H2O稀釋反應混合物且用乙酸乙酯萃取。 合併有機層且用鹽水洗滌。將有機層經MgSO4乾燥，過濾且濃縮。在0℃下將粗化合物溶解於甲醇(15mL)中，且添加K2CO3(904mg，6.54mmol)。在室溫下攪拌2h之後，用H2O稀釋反應混合物且用乙酸乙酯 萃取。將有機層經MgSO4乾燥，過濾且濃縮。將粗產物添加至矽膠管柱且用己烷/乙酸乙酯0%至30%溶離。蒸發收集之溶離份，獲得經Boc保護之化合物。在0℃下將化合物溶解於CH2Cl2(5mL)中，且添加TFA(1.5ml)。在室溫下攪拌2h之後，用20%Na2CO3水溶液淬滅反應混合物且用乙酸乙酯萃取。將有機層經MgSO4乾燥且過濾。於真空中濃縮濾液，得到呈白色非晶形形式之化合物9-13(538mg，1.88mmol，86%)，其不經純化即用於下一步驟。 Add a solution of Boc compound 9-12 (853mg, 2.19mmol) in THF (10mL) was stirred in a solution of the 2 O (0.761mL, 3.28mmol) and DMAP (80mg, 0.656mmol). After stirring for 1h, the reaction mixture was diluted with H 2 O and extracted with ethyl acetate. The organic layers were combined and washed with brine. The organic layer was dried over MgSO 4, filtered and concentrated. At 0 ℃ The crude compound was dissolved in methanol (15mL), and the added K 2 CO 3 (904mg, 6.54mmol ). After stirring for 2h at room temperature the reaction mixture was diluted with H 2 O and extracted with ethyl acetate. The organic layer was dried over MgSO 4, filtered and concentrated. The crude product was added to a silica gel column and was dissolved from 0% to 30% with hexane/ethyl acetate. The collected fractions were evaporated to give a Boc-protected compound. At 0 ℃ The compound was dissolved in CH 2 Cl 2 (5mL), and was added TFA (1.5ml). After stirring for 2h at room temperature, 20% Na 2 CO 3 aqueous reaction mixture was quenched and extracted with ethyl acetate. The organic layer was dried and filtered over MgSO 4. The filtrate was concentrated in vacuo to give crystals crystals crystals.

1H-NMR(400MHz,CDCl3)δ：1.65(s,3H),4.00-4.23(m,3H),4.70(s,1H),7.06(dd,J=12.0,8.0Hz,1H),7.14(t,J=8.0Hz,1H),7.28(m,1H),7.36(t,J=8.0Hz,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.65 (s, 3H), 4.00-4.23 (m, 3H), 4.70 (s, 1H), 7.06 (dd, J = 12.0,8.0Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 7.28 (m, 1H), 7.36 (t, J = 8.0 Hz, 1H).

步驟13 Step 13

在-10℃下向化合物9-13(538mg，1.88mmol)於TFA(2.2ml)中之溶液中添加硫酸(0.65ml，12.2mmol)。在-10℃下攪拌5分鐘之後，在-10℃下向反應混合物中添加HNO3(0.18ml，2.82mmol)。在-10℃下攪拌30分鐘之後，用K2CO3水溶液處理反應混合物。用AcOEt萃取水層，且經MgSO4乾燥有機層，過濾且濃縮。藉由超臨界流體層析(SFC)(Chiralpak(註冊商標)IC；具有0.1%二乙胺之0-65%甲基醇)純化粗產物，得到呈白色非晶形形式之化合物9-14(300mg，0.91mmol，48%)。 Sulfuric acid (0.65 ml, 12.2 mmol) was added to a solution of compound 9-13 (538 mg, 1.88 mmol) in EtOAc. After stirring at -10 ℃. 5 minutes, at -10 ℃ the reaction mixture HNO 3 (0.18ml, 2.82mmol). After stirring at -10 ° C for 30 minutes, the reaction mixture was treated with aqueous K 2 CO 3 . The aqueous layer was extracted with AcOEt, and organic layer was dried and MgSO 4, filtered and concentrated. The crude product was purified by supercritical fluid chromatography (SFC) (Chiralpak (registered trademark) IC; 0-65% methyl alcohol with 0.1% diethylamine) to give compound 9-14 (300 mg) as a white amorphous form. , 0.91 mmol, 48%).

1H-NMR(400MHz,CDCl3)δ：1.66(s,3H),4.04(m,1H),4.05-4.24(m,2H),4.68(s,1H),7.23(m,1H),8.21(m,1H),8.34(m,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.66 (s, 3H), 4.04 (m, 1H), 4.05-4.24 (m, 2H), 4.68 (s, 1H), 7.23 (m, 1H), 8.21 (m, 1H), 8.34 (m, 1H).

步驟14 Step 14

在室溫下在氫氣氛圍下攪拌化合物9-14(71mg，0.21mmol)、10%Pd/C(20mg)於MeOH(2ml)中之懸浮液。在相同溫度下攪拌2h之後，經由矽藻土(註冊商標)墊過濾混合物。於真空中濃縮濾液，得到呈白色非晶形形式之化合物9-15(63mg，0.21mmol，98%)，其不 經純化即用於下一步驟。 A suspension of compound 9-14 (71 mg, 0.21 mmol), 10% Pd / C (20 mg) in MeOH (2 mL). After stirring at the same temperature for 2 h, the mixture was filtered through a pad of diatomaceous earth (registered trademark). The filtrate was concentrated in vacuo to afford compound 9-15 (63 mg, 0.21 mmol, 98%) It was used in the next step after purification.

1H-NMR(400MHz,CDCl3)δ：1.61(s,3H),4.02-4.33(m,3H),4.69(s,1H),6.52(m,1H),6.64(m,1H),6.84(m,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.61 (s, 3H), 4.02-4.33 (m, 3H), 4.69 (s, 1H), 6.52 (m, 1H), 6.64 (m, 1H), 6.84 (m, 1H).

步驟15 Step 15

在室溫下向化合物9-15(63mg，0.21mmol)於CH2Cl2(2ml)中之溶液中添加5-氰基吡啶甲酸水合物(38.2mg，0.23mmol)、EDC(48mg，0.25mmol)及2mmol/L HCl(水溶液，0.11ml，0.209mmol)。在相同溫度下攪拌1h之後，用H2O處理反應混合物。用AcOEt萃取水層，且經MgSO4乾燥有機層，過濾且濃縮。將粗產物添加至矽膠管柱且用己烷/EtOAc 30%至70%溶離。蒸發收集之溶離份，獲得呈白色固體狀之化合物I-35(66mg，0.153mmol，73%)。 Was added 5-cyano-pyridine-carboxylic acid hydrate (38.2mg, 0.23mmol) solution of compound 9-15 (63mg, 0.21mmol) in CH 2 Cl 2 (2ml) in the solution at room temperature, EDC (48mg, 0.25mmol And 2 mmol/L HCl (aqueous solution, 0.11 ml, 0.209 mmol). After stirring at the same temperature for 1 h, the reaction mixture was treated with H 2 O. The aqueous layer was extracted with AcOEt, and organic layer was dried and MgSO 4, filtered and concentrated. The crude product was added to a silica gel column and was dissolved with hexane/EtOAc 30% to 70%. The collected fractions were evaporated to give compound I-35 (m.

實例10 合成化合物I-63 Example 10 Synthesis of Compound I-63

步驟1：合成化合物10-4 Step 1: Synthesis of Compound 10-4

在室溫下向3,3-二氟環丁烷甲酸(化合物10-1，3.00g，22.0mmol)於DMF(30ml)中之溶液中添加Cs2CO3(14.4g，44.1mmol)及BnBr(2.62ml，22.0mmol)。在50℃下攪拌20分鐘之後，用H2O處理混合物，且用AcOEt萃取水層。用H2O及鹽水洗滌經合併之有機層，經Na2SO4乾燥且過濾。於真空中濃縮濾液，得到呈黃色油狀之化合物10-2，其不經純化即用於下一步驟。 Add Cs 2 CO 3 (14.4 g, 44.1 mmol) and BnBr to a solution of 3,3-difluorocyclobutanecarboxylic acid (Compound 10-1, 3.00 g, 22.0 mmol) in DMF (30 mL) (2.62 ml, 22.0 mmol). After stirring at 50 ° C for 20 minutes, the mixture was treated with H 2 O and aqueous layer was extracted with AcOEt. H 2 O was washed with brine and the organic layers were combined, dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to afford compound 10-2 as a yellow oil.

在-78℃下向二異丙胺(2.91ml，20.5mmol)於THF(25ml)中之溶液中添加1.6mol/L n-BuLi(12.2ml，19.5mmol)。在相同溫度下攪拌30分鐘之後，添加THF(10ml)中之化合物10-2(3.30g，14.6mmol)，且攪拌此1h，接著添加THF(10ml)中之Ti(OiPr)3Cl(4.89ml，20.5mmol)。在相同溫度下攪拌10分鐘之後，向混合物中添加THF(10ml)中之10-3(2.35g，9.74mmol)。在相同溫度下攪拌混合物1h且用 NH4Cl飽和水溶液處理。用AcOEt萃取水層，且用鹽水洗滌合併之有機層，經Na2SO4乾燥且過濾。在真空中濃縮濾液。將粗產物添加至矽膠管柱且用己烷/EtOAc 30%溶離。蒸發收集之溶離份，獲得呈黃色油狀之化合物10-4(1.24g，2.65mmol，27%)。 To a solution of diisopropylamine (2.91 ml, 20.5 mmol) in THF (25 ml) was added 1.6 mol/L n- BuLi (12.2 ml, 19.5 mmol). After stirring for 30 minutes at the same temperature, compound 10-2 (3.30 g, 14.6 mmol) in THF (10 ml) was added, and the mixture was stirred for 1 h, then added Ti(OiPr) 3 Cl (4.89 ml) in THF (10 ml) , 20.5 mmol). After stirring at the same temperature for 10 minutes, 10-3 (2.35 g, 9.74 mmol) of THF (10 ml) was added to the mixture. The mixture was stirred at the same temperature for 1 h and treated with a saturated aqueous solution of NH 4 Cl. The aqueous layer was extracted with AcOEt, and the organic layers were combined and washed with the brine, dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo. The crude product was added to a silica gel column and was eluted with hexanes/EtOAc 30%. The collected fractions were evaporated to give compound 10-4 (1. 4 g, 2.

1H-NMR(400MHz,CDCl3)δ：1.24(s,9H),1.94(s,3H),2.87-3.33(m,4H),4.79(s,2H),5.15(s,1H),6.94-7.01(m,1H),7.03-7.08(m,1H),7.09-7.14(m,2H),7.22-7.39(m,5H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.24 (s, 9H), 1.94 (s, 3H), 2.87-3.33 (m, 4H), 4.79 (s, 2H), 5.15 (s, 1H), 6.94 -7.01 (m, 1H), 7.03-7.08 (m, 1H), 7.09-7.14 (m, 2H), 7.22 - 7.39 (m, 5H).

步驟2：合成化合物10-6 Step 2: Synthesis of compound 10-6

在室溫下向化合物10-4(1.24g，2.65mmol)於MeOH(8ml)中之溶液中添加二烷(0.995ml，3.98mmol)中之4mol/L HCl。在相同溫度下攪拌1h之後，用NaHCO3水溶液處理反應混合物，且用CHCl3萃取水層。用H2O及鹽水洗滌合併之有機層，經Na2SO4乾燥且過濾。於真空中濃縮濾液，得到呈褐色油狀之化合物10-5，其不經純化即用於下一步驟。 To the solution of compound 10-4 (1.24 g, 2.65 mmol) in MeOH (8 mL) 4 mol/L HCl in alkane (0.995 ml, 3.98 mmol). After stirring at the same temperature for 1 h, the reaction mixture was treated with aqueous NaHCO 3 and aqueous layer was extracted with CHCl 3 . With 2 O and the combined organic layers were washed with brine H, dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to afford compound 10-5, m.

在室溫下向化合物10-5於MeOH(10ml)中之溶液中添加Boc2O(1.85ml，7.96mmol)。在60℃下攪拌16h之後，濃縮反應混合物。將所得殘餘物添加至矽膠管柱中且用己烷/EtOAc 0%至10%溶離。蒸發收集之溶離份，獲得呈無色油狀之10-6(914mg，1.97mmol，74%)。 Boc 2 O (1.85 ml, 7.96 mmol) was added to a solution of compound 10-5 in MeOH (10 mL). After stirring at 60 ° C for 16 h, the reaction mixture was concentrated. The residue obtained was added to a silica gel column and lysed with hexane / EtOAc from 0% to 10%. The collected fractions were evaporated to give 10-6 ( 940 mg, 1.97 mmol, 74%) as a colourless oil.

1H-NMR(400MHz,CDCl3)δ：1.24(s,9H),1.94(s,3H),2.88-3.32(m,4H),4.79(s,2H),5.15(s,1H),6.94-7.01(m,1H),7.03-7.08(m,1H),7.10-7.14(m,2H),7.39-7.22(m,5H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.24 (s, 9H), 1.94 (s, 3H), 2.88-3.32 (m, 4H), 4.79 (s, 2H), 5.15 (s, 1H), 6.94 -7.01 (m, 1H), 7.03-7.08 (m, 1H), 7.10-7.14 (m, 2H), 7.39-7.22 (m, 5H).

步驟3：合成化合物10-7 Step 3: Synthesis of compound 10-7

在0℃下向化合物10-6(914mg，1.97mmol)於THF(9ml)中之溶液中添加THF(1.97ml，5.92mmol)及MeOH(0.240ml，5.92mmol)中之3mol/L LiBH4。在室溫下攪拌30分鐘之後，用H2O及AcOH處理混合物。用AcOEt萃取水層，且用鹽水洗滌合併之有機層，經Na2SO4乾 燥且過濾。在真空中濃縮濾液。將粗產物添加至矽膠管柱且用己烷/EtOAc 20%溶離。蒸發收集之溶離份，獲得呈白色固體狀之化合物10-7(693mg，1.93mmol，98%)。 To a solution of compound 10-6 (914 mg, 1.97 mmol) in THF (9 ml), THF (1.97 ml, 5.92 mmol) and MeOH (0.240 ml, 5.92 mmol) of 3 mol/L LiBH 4 was added at 0 °C. After stirring at room temperature for 30 minutes, the mixture was treated with H 2 O and AcOH. The aqueous layer was extracted with AcOEt, and the organic layers were combined and washed with the brine, dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo. The crude product was added to a silica gel column and was dissolved with hexanes/EtOAc 20%. The collected fractions were evaporated to give compound 10-7 (693 mg, 1.

1H-NMR(400MHz,CDCl3)δ：1.38(s,9H),1.99(d,J=2.5Hz,3H),2.04-2.19(m,1H),2.46-2.60(m,1H),2.78(q,J=14.4Hz,1H),2.92(q,J=14.4Hz,1H),3.60(d,J=10.5Hz,1H),3.77(d,J=10.5Hz,1H),6.51(s,1H),6.99-7.06(m,1H),7.11-7.16(m,1H),7.30-7.23(m,1H),7.35(t,J=7.3Hz,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.38 (s, 9H), 1.99 (d, J = 2.5Hz, 3H), 2.04-2.19 (m, 1H), 2.46-2.60 (m, 1H), 2.78 (q, J = 14.4 Hz, 1H), 2.92 (q, J = 14.4 Hz, 1H), 3.60 (d, J = 10.5 Hz, 1H), 3.77 (d, J = 10.5 Hz, 1H), 6.51 (s) , 1H), 6.99-7.06 (m, 1H), 7.11-7.16 (m, 1H), 7.30-7.23 (m, 1H), 7.35 (t, J = 7.3 Hz, 1H).

步驟4：合成化合物10-8 Step 4: Synthesis of compound 10-8

在室溫下向化合物10-7(693mg，1.93mmol)於CH2Cl2(7ml)中之溶液中添加DMP(2.13g，5.01mmol)。在相同溫度下攪拌16h之後，用NaHCO3水溶液及NaHSO3水溶液處理混合物。用CHCl3萃取水層，且用鹽水洗滌合併之有機層，經Na2SO4乾燥且過濾。在真空中濃縮濾液。將粗產物添加至矽膠管柱且用己烷/EtOAc 20%溶離。蒸發收集之溶離份，獲得呈白色固體狀之化合物10-8(356mg，0.996mmol，52%)。 DMP (2.13 g, 5.01 mmol) was added to a solution of compound 10-7 (693 mg, 1.93 mmol) in CH 2 Cl 2 (7 ml). After stirring at the same temperature for 16 h, the mixture was treated with aqueous NaHCO 3 and aqueous NaHSO 3 . The organic layer was washed with brine and the combined aqueous layer was extracted with CHCl 3, dried Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo. The crude product was added to a silica gel column and was dissolved with hexanes/EtOAc 20%. The collected fractions were evaporated to give compound 10-8 (356 g, <RTIgt;

1H-NMR(400MHz,CDCl3)δ：1.38(s,9H),1.88(d,J=1.6Hz,3H),2.79-3.01(m,4H),5.11(s,1H),7.03-7.11(m,1H),7.13-7.20(m,1H),7.34-7.22(m,2H),9.57(s,1H)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.38 (s, 9H), 1.88 (d, J = 1.6 Hz, 3H), 2.79-3.01 (m, 4H), 5.11 (s, 1H), 7.03-7.11 (m, 1H), 7.13-7.20 (m, 1H), 7.34-7.22 (m, 2H), 9.57 (s, 1H).

步驟5：合成化合物10-9 Step 5: Synthesis of Compounds 10-9

在室溫下向溴化甲基三苯基鏻(890mg，2.49mmol)於甲苯(8ml)中之溶液中添加THF(2.29ml，2.29mmol)中之1.00mol/L t-BuOK溶液。在相同溫度下攪拌1h之後，在10℃下向混合物中添加化合物10-8(356mg，0.996mmol)於甲苯(4ml)中之溶液，且在室溫下攪拌混合物1h。用NH4Cl飽和水溶液處理反應混合物，且用AcOEt萃取水層。用鹽水洗滌經合併之有機層，經Na2SO4乾燥且過濾。在真空中濃 縮濾液。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至20%溶離。蒸發收集之溶離份，獲得呈無色油狀之化合物10-9(304mg，0.855mmol，86%)。 A solution of 1.00 mol/L t- BuOK in THF (2.29 ml, 2.29 mmol) was added to a solution of methyltriphenylphosphonium bromide (890 mg, 2.49 mmol) in toluene (8 ml). After stirring for 1 h at the same temperature, a solution of compound 10-8 (356 mg, 0.996 mmol) in toluene (4 ml) was added to the mixture, and the mixture was stirred at room temperature for 1 h. The reaction mixture was treated with a saturated aqueous solution of NH 4 Cl and aqueous layer was extracted with AcOEt. The combined organic layers were washed with brine, dried over Na 2 CH 4 and filtered. The filtrate was concentrated in vacuo. The crude product was added to a silica gel column and was eluted with hexanes/EtOAc from 0% to 20%. The collected fractions were evaporated to give compound 10-9 (304 mg, <RTIgt;

1H-NMR(400MHz,CDCl3)δ：1.35(s,9H),1.90(d,J=2.4Hz,3H),2.41-2.59(m,2H),2.82-3.01(m,2H),4.99(s,1H),5.23(d,J=17.2Hz,1H),5.35(d,J=10.5Hz,1H),5.76(dd,J=17.2,10.5Hz,1H),7.02(dd,J=13.1,8.2Hz,1H),7.11(t,J=7.1Hz,1H),7.29-7.19(m,2H)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.35 (s, 9H), 1.90 (d, J = 2.4 Hz, 3H), 2.41-2.59 (m, 2H), 2.82-3.01 (m, 2H), 4.99 (s, 1H), 5.23 (d, J = 17.2 Hz, 1H), 5.35 (d, J = 10.5 Hz, 1H), 5.76 (dd, J = 17.2, 10.5 Hz, 1H), 7.02 (dd, J = 13.1, 8.2 Hz, 1H), 7.11 (t, J = 7.1 Hz, 1H), 7.29-7.19 (m, 2H).

步驟6：合成化合物10-11 Step 6: Synthesis of Compound 10-11

在室溫下攪拌化合物10-9(304mg，0.855mmol)於二烷(2.14ml，8.55mmol)中之4mol/L HCl中之溶液30分鐘。用NaHCO3水溶液處理反應混合物且用AcOEt萃取水層。用H2O及鹽水洗滌經合併之有機層，經Na2SO4乾燥且過濾。於真空中濃縮濾液，得到呈褐色油狀之化合物10-10，其不經純化即用於下一步驟。 Stir compound 10-9 (304 mg, 0.855 mmol) in two at room temperature A solution of 4 mol/L HCl in alkane (2.14 ml, 8.55 mmol) was taken for 30 min. The reaction was treated with aqueous NaHCO 3 mixture and the aqueous layer was extracted with AcOEt. H 2 O was washed with brine and the organic layers were combined, dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to give compound 10-10, m.

在室溫下向化合物10-10於CH2Cl2(2ml)中之溶液中添加異硫氰酸苯甲醯酯(0.176ml，1.28mmol)。在相同溫度下攪拌15h之後，濃縮反應混合物。將所得殘餘物添加至矽膠管柱中且用己烷/EtOAc 0%至20%溶離。蒸發收集之溶離份，獲得呈白色非晶形形式之化合物10-11(347mg，0.829mmol，97%)。 10-10 to the compound at room temperature to CH 2 Cl 2 (2ml) was added in the benzoyl isothiocyanate (0.176ml, 1.28mmol). After stirring at the same temperature for 15 h, the reaction mixture was concentrated. The resulting residue was added to a silica gel column and was eluted with hexane / EtOAc from 0% to 20%. The collected fractions were evaporated to give compound 10-11 (347 mg, <RTIgt;

1H-NMR(400MHz,CDCl3)δ：1.56(s,9H),2.16(d,J=2.3Hz,3H),2.56-2.73(m,2H),2.85-3.01(m,2H),5.42(d,J=17.3Hz,1H),5.46(d,J=10.5Hz,1H),5.89(dd,J=17.3,10.5Hz,1H),7.02-7.08(m,1H),7.14-7.19(m,1H),7.21-7.34(m,2H),7.52(t,J=7.4Hz,2H),7.63(t,J=7.4Hz,1H),7.86(d,J=7.4Hz,2H),8.85(s,1H),11.55(s,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.56 (s, 9H), 2.16 (d, J = 2.3Hz, 3H), 2.56-2.73 (m, 2H), 2.85-3.01 (m, 2H), 5.42 (d, J = 17.3 Hz, 1H), 5.46 (d, J = 10.5 Hz, 1H), 5.89 (dd, J = 17.3, 10.5 Hz, 1H), 7.02-7.08 (m, 1H), 7.14 - 7.19 ( m,1H), 7.21 - 7.34 (m, 2H), 7.52 (t, J = 7.4 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.86 (d, J = 7.4 Hz, 2H), 8.85 (s, 1H), 11.55 (s, 1H).

步驟7：合成化合物10-12 Step 7: Synthesis of Compound 10-12

在0℃下向碘(421mg，1.66mmol)於MeCN(9ml)中之溶液中添加MeCN(5ml)中之化合物10-11(347mg，0.829mmol)。在相同溫度下攪拌2h之後，用NaHCO3及Na2S2O3水溶液處理反應混合物。用AcOEt萃取水層。用鹽水洗滌合併之有機層，經Na2SO4乾燥，過濾且濃縮。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至15%溶離。蒸發收集之溶離份，獲得呈白色非晶形形式之化合物10-12(343mg，0.630mmol，76%)。 To a solution of iodine (421 mg, 1.66 mmol) in MeCN (9 mL), EtOAc (EtOAc) After stirring at the same temperature for 2 h, the reaction mixture was treated with aqueous NaHCO 3 and Na 2 S 2 O 3 . The aqueous layer was extracted with AcOEt. , Dried combined organic layers were washed with brine, Na 2 SO 4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with hexanes/EtOAc from 0% to 15%. The collected fractions were evaporated to give compound 10-12 (343 mg, 0.630 mmol, 76%).

1H-NMR(400MHz,CDCl3)δ：1.83(s,3H),2.74-2.99(m,3H),3.29(t,J=11.1Hz,1H),3.36-3.47(m,2H),3.74(dd,J=10.0,2.5Hz,1H),7.12(dd,J=12.7,8.2Hz,1H),7.20(t,J=7.7Hz,1H),7.29-7.41(m,2H),7.44(t,J=7.5Hz,2H),7.52(t,J=7.5Hz,1H),8.22(d,J=7.5Hz,2H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.83 (s, 3H), 2.74-2.99 (m, 3H), 3.29 (t, J = 11.1Hz, 1H), 3.36-3.47 (m, 2H), 3.74 (dd, J =10.0, 2.5 Hz, 1H), 7.12 (dd, J =12.7, 8.2 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.29-7.41 (m, 2H), 7.44 ( t, J = 7.5 Hz, 2H), 7.52 (t, J = 7.5 Hz, 1H), 8.22 (d, J = 7.5 Hz, 2H).

步驟8：合成化合物10-13 Step 8: Synthesis of Compound 10-13

在室溫下向化合物10-12(343mg，0.630mmol)於甲苯(5ml)中之溶液中添加Bu3SnH(0.251ml，0.945mmol)及AIBN(10.4mg，0.0630mmol)。在80℃下攪拌1h之後，濃縮反應混合物。將所得殘餘物添加至胺基矽膠管柱中且用己烷/EtOAc 0%至20%溶離。蒸發收集之溶離份，獲得呈白色非晶形形式之化合物10-13(212mg，0.507mmol，80%)。 Add a solution of compound 10-12 (343mg, 0.630mmol) in toluene (5ml) in a solution of Bu 3 SnH (0.251ml, 0.945mmol) and AIBN (10.4mg, 0.0630mmol). After stirring at 80 ° C for 1 h, the reaction mixture was concentrated. The residue obtained was added to an amine oxime column and lysed with hexane / EtOAc from 0% to 20%. The collected fractions were evaporated to give compound 10-13 (212 mg, 0.507 mmol, 80%).

1H-NMR(400MHz,CDCl3)δ：1.33(d,J=6.9Hz,3H),1.85(s,3H),2.81(q,J=12.5Hz,1H),2.88-3.01(m,1H),3.23(q,J=6.9Hz,1H),3.35(q,J=12.5Hz,1H),7.10(dd,J=12.5,8.2Hz,1H),7.17(t,J=7.6Hz,1H),7.32-7.38(m,2H),7.43(t,J=7.5Hz,2H),7.51(t,J=7.5Hz,1H),8.22(d,J=7.5Hz,2H),12.02(br s,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.33 (d, J = 6.9Hz, 3H), 1.85 (s, 3H), 2.81 (q, J = 12.5Hz, 1H), 2.88-3.01 (m, 1H ), 3.23 (q, J = 6.9 Hz, 1H), 3.35 (q, J = 12.5 Hz, 1H), 7.10 (dd, J = 12.5, 8.2 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H) ), 7.32 - 7.38 (m, 2H), 7.43 (t, J = 7.5 Hz, 2H), 7.51 (t, J = 7.5 Hz, 1H), 8.22 (d, J = 7.5 Hz, 2H), 12.02 (br s, 1H).

步驟9：合成化合物10-14 Step 9: Synthesis of Compound 10-14

在室溫下向1-5(212mg，0.507mmol)於MeOH(1ml)及THF(1 mL)中之溶液中添加水合肼(0.246ml，5.07mmol)。在相同溫度下攪拌13小時後，濃縮反應混合物。將所得殘餘物添加至胺基矽膠管柱中且用己烷/EtOAc 10%至50%溶離。蒸發收集之溶離份，獲得呈白色非晶形形式之化合物10-14(150mg，0.477mmol，94%)。 1-5 (212 mg, 0.507 mmol) in MeOH (1 ml) and THF (1) Hydrazine hydrate (0.246 ml, 5.07 mmol) was added to the solution in mL). After stirring at the same temperature for 13 hours, the reaction mixture was concentrated. The resulting residue was added to an amine oxime column and lysed with hexanes/EtOAc 10% to 50%. The collected fractions were evaporated to give compound 10-14 (150 mg, 0.477 mmol, 94%).

1H-NMR(400MHz,CDCl3)δ：1.24(d,J=6.8Hz,3H),1.72(s,3H),2.67-2.81(m,3H),3.20(q,J=6.8Hz,1H),3.27-3.42(m,1H),7.02(dd,J=12.7,8.0Hz,1H),7.11(t,J=7.5Hz,1H),7.22-7.28(m,1H),7.32(t,J=8.0Hz,1H)。 1 H-NMR (400MHz, CDCl 3) δ: 1.24 (d, J = 6.8Hz, 3H), 1.72 (s, 3H), 2.67-2.81 (m, 3H), 3.20 (q, J = 6.8Hz, 1H ), 3.27-3.42 (m, 1H), 7.02 (dd, J = 12.7, 8.0 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 7.22 - 7.28 (m, 1H), 7.32 (t, J = 8.0Hz, 1H).

步驟10：合成化合物10-16 Step 10: Synthesis of Compounds 10-16

在-20℃下向1-6於TFA(1.3ml)中之溶液中添加硫酸(0.318ml，5.96mmol)。在0℃下攪拌5分鐘之後，將反應混合物在-20℃下添加至HNO3(0.0320ml，0.716mmol)中。在0℃下攪拌20分鐘之後，用K2CO3水溶液處理反應混合物。用AcOEt萃取水層且經Na2SO4乾燥有機層。於真空中濃縮濾液，得到呈黃色油狀之化合物1-15，其不經純化即用於下一步驟。 Sulfuric acid (0.318 ml, 5.96 mmol) was added to a solution of 1-6 in TFA (1.3 mL). After stirring at 0 ℃ 5 minutes, the reaction mixture was added to HNO 3 (0.0320ml, 0.716mmol) at -20 ℃. After stirring at 0 ° C for 20 minutes, the reaction mixture was treated with aqueous K 2 CO 3 . The aqueous layer was extracted with EtOAc and dried over Na 2 SO 4 . The filtrate was concentrated in vacuo to afford compound 1-15 as a yellow oil.

在室溫下向化合物10-15於THF(2ml)中之溶液中添加Boc2O(0.331ml，1.43mmol)及DMAP(23.3mg，0.190mmol)。在相同溫度下攪拌30分鐘之後，在真空下濃縮混合物。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至20%溶離。蒸發收集之溶離份，獲得呈白色非晶形形式之10-16(252mg，0.450mmol，95%)。 To a solution of compound 10-15 (2ml) in of THF was added Boc 2 O (0.331ml, 1.43mmol) and DMAP (23.3mg, 0.190mmol) at room temperature. After stirring at the same temperature for 30 minutes, the mixture was concentrated under vacuum. The crude product was added to a silica gel column and was eluted with hexanes/EtOAc from 0% to 20%. The collected fractions were evaporated to give 10-16 (252 mg, 0.450 mmol, 95%) as white white.

1H-NMR(400MHz,CDCl3)δ：1.36(d,J=6.9Hz,3H),1.55(s,18H),1.85(d,J=1.6Hz,3H),2.71-2.94(m,3H),3.21(q,J=15.7Hz,1H),3.33(q,J=6.9Hz,1H),7.20(dd,J=11.2,9.0Hz,1H),8.22-8.15(m,1H),8.57(dd,J=6.8,2.8Hz,1H)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.36 (d, J = 6.9 Hz, 3H), 1.55 (s, 18H), 1.85 (d, J = 1.6 Hz, 3H), 2.71-2.94 (m, 3H) ), 3.21 (q, J = 15.7 Hz, 1H), 3.33 (q, J = 6.9 Hz, 1H), 7.20 (dd, J = 11.2, 9.0 Hz, 1H), 8.22 - 8.15 (m, 1H), 8.57 (dd, J = 6.8, 2.8 Hz, 1H).

步驟11：合成化合物10-17 Step 11: Synthesis of Compound 10-17

在室溫下向化合物10-16(252mg，0.450mmol)於EtOH(2ml)、 THF(1ml)及H2O(1ml)中之溶液中添加NH4Cl(289mg，5.40mmol)及Fe(201mg，3.60mmol)。在60℃下攪拌1h之後，用H2O處理混合物且經由矽藻土(註冊商標)墊過濾。用AcOEt萃取水層，且經Na2SO4乾燥有機層，過濾且濃縮。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至30%溶離。蒸發收集之溶離份，獲得呈白色非晶形形式之化合物10-17(177mg，0.334mmol，74%)。 , In the 2 O (1ml) solution of THF (1ml) was added to the compound and H 10-16 (252mg, 0.450mmol) in EtOH (2ml) NH 4 Cl at room temperature (289mg, 5.40mmol) and Fe (201mg , 3.60mmol). After stirring at 60 ° C for 1 h, the mixture was treated with H 2 O and filtered through a pad of Celite (registered trademark). The aqueous layer was extracted with AcOEt, and organic layer and dried over Na 2 SO 4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with hexane / EtOAc from 0% to 30%. The collected fractions were evaporated to give compound 10-17 (177 mg, 0.334 mmol, 74%).

1H-NMR(400MHz,CDCl3)δ：1.27(d,J=7.0Hz,3H),1.54(s,18H),1.86(d,J=2.5Hz,3H),2.63-2.87(m,3H),3.28-3.47(m,2H),3.61(s,2H),6.56-6.50(m,1H),6.82(dd,J=12.5,8.5Hz,1H),7.03(dd,J=7.0,2.8Hz,1H)。 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.27 (d, J = 7.0 Hz, 3H), 1.54 (s, 18H), 1.86 (d, J = 2.5 Hz, 3H), 2.63 - 2.87 (m, 3H) ), 3.28-3.47 (m, 2H) , 3.61 (s, 2H), 6.56-6.50 (m, 1H), 6.82 (dd, J = 12.5,8.5Hz, 1H), 7.03 (dd, J = 7.0,2.8 Hz, 1H).

步驟10：合成化合物10-18 Step 10: Synthesis of Compound 10-18

在室溫下向化合物10-17(50.0mg，0.0940mmol)於DMF(1ml)中之溶液中添加5-氟吡啶甲酸(13.3mg，0.0940mmol)、HATU(43.1mg，0.113mmol)及DIPEA(0.0330ml，0.189mmol)。在相同溫度下攪拌30分鐘之後，用H2O處理反應混合物。用AcOEt萃取水層，且經Na2SO4乾燥有機層，過濾且濃縮。將粗產物添加至矽膠管柱中且用己烷/EtOAc 0%至30%溶離。蒸發收集之溶離份，獲得呈無色油狀之化合物10-18(58.0mg，0.0890mmol，94%)。 Add 5-fluoropicolinic acid (13.3 mg, 0.0940 mmol), HATU (43.1 mg, 0.113 mmol) and DIPEA to a solution of compound 10-17 (50.0 mg, 0.0940 mmol) in DMF (1 mL) 0.0330 ml, 0.189 mmol). After stirring at the same temperature for 30 minutes, the reaction mixture was treated with H 2 O. The aqueous layer was extracted with AcOEt, and organic layer and dried over Na 2 SO 4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with hexane / EtOAc from 0% to 30%. The collected fractions were evaporated to give compound 10-18 (58.0 mg, <RTIgt;

1H-NMR(400MHz,CDCl3)δ：1.29(d,J=7.0Hz,3H),1.60(s,18H),1.92(s,3H),2.70-2.93(m,3H),3.33-3.49(m,2H),7.08(dd,J=12.2,8.8Hz,1H),7.58(td,J=8.8,2.8Hz,1H),7.72(dd,J=7.1,2.8Hz,1H),8.44-8.31(m,3H),10.03(s,1H)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.29 (d, J = 7.0 Hz, 3H), 1.60 (s, 18H), 1.92 (s, 3H), 2.70-2.93 (m, 3H), 3.33-3.49 (m, 2H), 7.08 (dd, J = 12.2, 8.8 Hz, 1H), 7.58 (td, J = 8.8, 2.8 Hz, 1H), 7.72 (dd, J = 7.1, 2.8 Hz, 1H), 8.44 8.31 (m, 3H), 10.03 (s, 1H).

步驟11：合成化合物I-63 Step 11: Synthesis of Compound I-63

在室溫下向化合物10-18(58.0mg，0.0890mmol)於CH2Cl2(0.7ml)中之溶液中添加TFA(0.226ml，2.93mmol)。在相同溫度下攪拌17h之後，用K2CO3水溶液處理反應混合物。用AcOEt萃取水層且經 Na2SO4乾燥有機層，過濾且濃縮，獲得呈白色固體狀之化合物I-63(34.0mg，0.0750mmol，85%)。 TFA was added a solution of compound 10-18 (58.0mg, 0.0890mmol) in CH 2 Cl 2 (0.7ml) in the solution at room temperature (0.226ml, 2.93mmol). After stirring at the same temperature for 17 h, the reaction mixture was treated with aqueous K 2 CO 3 . The aqueous layer was extracted with AcOEt and the combined organic layer was dried over Na 2 SO 4, filtered and concentrated to give a white solid of Compound I-63 (34.0mg, 0.0750mmol, 85%).

1H-NMR(400MHz,CDCl3)δ：1.27(d,J=7.0Hz,3H),1.74(s,3H),2.67-2.85(m,3H),3.24-3.42(m,2H),7.06(dd,J=11.9,8.7Hz,1H),7.44(dd,J=7.0,2.6Hz,1H),7.59(td,J=8.7,2.6Hz,1H),7.93-7.87(m,1H),8.33(dd,J=8.7,4.6Hz,1H),8.46(d,J=2.6Hz,1H),9.76(s,1H)。 1 H-NMR (400MHz, CDCl 3 ) δ: 1.27 (d, J = 7.0 Hz, 3H), 1.74 (s, 3H), 2.67-2.85 (m, 3H), 3.24 - 3.42 (m, 2H), 7.06 (dd, J=11.9, 8.7 Hz, 1H), 7.44 (dd, J=7.0, 2.6 Hz, 1H), 7.59 (td, J=8.7, 2.6 Hz, 1H), 7.93-7.87 (m, 1H), 8.33 (dd, J = 8.7, 4.6 Hz, 1H), 8.46 (d, J = 2.6 Hz, 1H), 9.76 (s, 1H).

實例11 合成化合物I-40 Example 11 Synthesis of Compound I-40

步驟1 step 1

在室溫下向化合物11-1(16.1g，46.5mmol)於甲醇(160ml)中之溶液中添加HCl-二烷(4M，16.3ml，65.0mmol)。在室溫下攪拌1.5h之後，濃縮反應混合物且用NaHCO3飽和水溶液淬滅。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮，獲得化合物11-2(12.8g，定量)。獲得之化合物11-2不經進一步純化即用於下一反應。 Add HCl-II to a solution of compound 11-1 (16.1 g, 46.5 mmol) in methanol (160 ml) at room temperature Alkane (4M, 16.3 ml, 65.0 mmol). After stirring for 1.5h at room temperature, the reaction mixture was concentrated and washed with saturated aqueous NaHCO 3 was quenched. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated to afford compound 11-2 (12.8 g, quantitative). The obtained compound 11-2 was used in the next reaction without further purification.

LC/MS(Shimadzu)：RT 0.80,MS計算值244.11(M+H+)，實驗值244.00。 </ RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI>

步驟2 Step 2

在室溫下向化合物11-2(12.8g，46.5mmol)於甲醇(55ml)中之溶液中添加Boc2O(32.4ml，140mmol)。在60℃下攪拌4h之後，濃縮反應混合物。藉由矽膠層析純化殘餘物，獲得化合物11-3(21.35g，定量，包括Boc2O，化合物3：Boc2O=1：0.8)。 In the solution was added Boc 2 O (32.4ml, 140mmol) solution of compound 11-2 (12.8g, 46.5mmol) in methanol (55 ml of) at room temperature. After stirring at 60 ° C for 4 h, the reaction mixture was concentrated. The residue was purified by silica gel chromatography to give compound 11-3 (21.35 g, quantitative, </ RTI> Boc 2 O, Compound 3: Boc 2 O = 1:0.8).

1H-NMR(CDCl3)δ：1.03(brs,3H),1.39(brs,9H),1.96(brs,3H),4.06(brs,2H),5.34(d,J=47.2Hz,1H),5.70(brs,1H),7.04(m,1H),7.11(m,1H),7.25-7.35(m,2H)。 1 H-NMR (CDCl 3 ) δ: 1.03 (brs, 3H), 1.39 (brs, 9H), 1.96 (brs, 3H), 4.06 (brs, 2H), 5.34 (d, J = 47.2 Hz, 1H), 5.70 (brs, 1H), 7.04 (m, 1H), 7.11 (m, 1H), 7.25-7.35 (m, 2H).

步驟3 Step 3

在-65℃下向化合物11-3(11.4g，24.7mmol，包括Boc2O)於CH2Cl2(110ml)中之溶液中添加DIBAL(1.02M，於甲苯中，107ml，109mmol)。在-65℃下攪拌50分鐘之後，用AcOEt及H2O中之羅謝爾鹽(93g，331mmol)淬滅反應混合物。在室溫下攪拌1.5h之後，用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮，獲得化合物11-4(7.87g，定量)。獲得之化合物11-4不經進一步純化即用於下一反應。 Was added at -65 ℃ solution of compound 11-3 (11.4g, 24.7mmol, including Boc 2 O) in the in CH 2 Cl 2 (110ml) a solution of DIBAL (1.02M, in toluene, 107ml, 109mmol). After stirring at -65 ℃ 50 min with AcOEt and H 2 O in the Rochelle salt (93g, 331mmol) The reaction mixture was quenched. After stirring at room temperature for 1.5 h, the aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated to afford compound 11-4 ( 7.78 g, quantitative). The obtained compound 11-4 was used in the next reaction without further purification.

1H-NMR(CDCl3)δ：1.39(s,9H),1.74(s,3H),5.07(s,1H),5.53(d,J=46.8Hz,1H),7.08(m,1H),7.16(m,1H),7.30(m,1H),7.37(m,1H),9.55(d,J=9.0Hz,1H)。 1 H-NMR (CDCl 3 ) δ: 1.39 (s, 9H), 1.74 (s, 3H), 5.07 (s, 1H), 5.53 (d, J = 46.8 Hz, 1H), 7.08 (m, 1H), 7.16 (m, 1H), 7.30 (m, 1H), 7.37 (m, 1H), 9.55 (d, J = 9.0 Hz, 1H).

步驟4 Step 4

在室溫下向化合物11-4(7.87g，24.7mmol)及2-溴-2,2-二氟乙酸乙酯(15.0g，74.1mmol)於THF(150ml)中之溶液中添加鋅(4.84g，74.1mmol)。在70℃下攪拌1.5h之後，將反應混合物冷卻至0℃且用NH4Cl飽和水溶液淬滅。經由矽藻土(註冊商標)墊過濾所得混合物且用AcOEt洗滌。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物11-5(1.40g，4.01mmol，16%，4個步驟)。 To a solution of compound 11-4 (7.87 g, 24.7 mmol) and ethyl 2-bromo-2,2-difluoroacetate (15.0 g, 74.1 mmol) in THF (150 mL) g, 74.1 mmol). After stirring for 1.5h at 70 ℃, the reaction mixture was cooled to 0 ℃ and treated with saturated aqueous NH 4 Cl quenched. The resulting mixture was filtered through a pad of diatomaceous earth (registered trademark) and washed with AcOEt. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to afford compound 11-5 (1.40 g, 4.01 mmol, 16%, 4 steps).

1H-NMR(CDCl3)δ：1.34(t,J=7.2Hz,3H),1.78(s,3H),4.34(q,J=7.2Hz,2H),4.40(ddd,J=28.5,13.7,6.3Hz,1H),5.49(d,J=47.4Hz,1H),5.83(s,1H),7.15(m,1H),7.28(m,1H),7.42(m,1H),7.51(m,1H)。 1 H-NMR (CDCl 3 ) δ: 1.34 (t, J = 7.2 Hz, 3H), 1.78 (s, 3H), 4.34 (q, J = 7.2 Hz, 2H), 4.40 (ddd, J = 28.5, 13.7) , 6.3 Hz, 1H), 5.49 (d, J = 47.4 Hz, 1H), 5.83 (s, 1H), 7.15 (m, 1H), 7.28 (m, 1H), 7.42 (m, 1H), 7.51 (m) , 1H).

步驟5 Step 5

在室溫下向化合物11-5(1.40g，4.01mmol)於THF(28ml)中之溶液中添加LiBH4(175mg，8.02mmol)。在室溫下攪拌45分鐘之後，用NH4Cl飽和水溶液淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物11-6(740mg，2.41mmol，60%)。 (, 4.01mmol 1.40g) in THF was added LiBH 4 (175mg, 8.02mmol) ( 28ml) in the solution at a solution of compound 11-5. After stirring at room temperature for 45 minutes, treated with saturated aqueous NH 4 Cl the reaction mixture was quenched. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to afford compound 11-6 (740 mg, 2.41 mmol, 60%).

1H-NMR(CDCl3)δ：1.79(s,3H),1.97(t,J=7.1Hz,1H),3.84-4.11(m,2H),4.28(ddd,J=30.0,13.2,6.4Hz,1H),5.47(d,J=46.9Hz,1H),5.69(s,1H),7.15(m,1H),7.27(m,1H),7.41(m,1H),7.50(m,1H)。 1 H-NMR (CDCl 3 ) δ: 1.79 (s, 3H), 1.97 (t, J = 7.1 Hz, 1H), 3.84-4.11 (m, 2H), 4.28 (ddd, J = 30.0, 13.2, 6.4 Hz , 1H), 5.47 (d, J = 46.9 Hz, 1H), 5.69 (s, 1H), 7.15 (m, 1H), 7.27 (m, 1H), 7.41 (m, 1H), 7.50 (m, 1H) .

步驟6 Step 6

在室溫下向化合物11-6(850mg，2.77mmol)、PPh3(2.90g，11.1mmol)及咪唑(753mg，11.1mmol)於THF(17ml)中之溶液中添加碘(2.81g，11.1mmol)。在80℃下攪拌16h之後，將反應混合物冷卻至0℃且用Na2S2O3水溶液淬滅。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物11-7(1.07g，2.57mmol，93%)。 To a solution of the compound 11-6 (850 mg, 2.77 mmol), PPh 3 (2.90 g, 11.1 mmol) and imidazole (753 mg, 11.1 mmol) in THF (17 ml), EtOAc (2.81 g, 11.1 mmol) ). After stirring for 16h at 80 ℃, the reaction mixture was cooled to 0 ℃ and treated with Na 2 S 2 O 3 aq quenched. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to afford Compound 11-7 (1.07 g, 2.57 mmol, 93%).

1H-NMR(CDCl3)δ：1.79(s,3H),3.56-3.74(m,2H),4.29(dt,J=29.5,7.6Hz,1H),5.41(d,J=47.2Hz,1H),5.72(s,1H),7.16(m,1H),7.29(m,1H),7.43(m,1H),7.50(m,1H)。 1 H-NMR (CDCl 3 ) δ: 1.79 (s, 3H), 3.56-3.74 (m, 2H), 4.29 (dt, J = 29.5, 7.6 Hz, 1H), 5.41 (d, J = 47.2 Hz, 1H) ), 5.72 (s, 1H), 7.16 (m, 1H), 7.29 (m, 1H), 7.43 (m, 1H), 7.50 (m, 1H).

步驟7 Step 7

在室溫下向化合物11-7(1.07g，2.57mmol)及Boc2O(1.19ml，5.13mmol)於CH2Cl2(20ml)中之溶液中添加DMAP(157mg，1.28mmol)。在室溫下攪拌45分鐘之後，濃縮反應混合物。藉由矽膠層析純化殘餘物，獲得化合物11-8(1.33g，2.57mmol，100%)。 Add a solution of compound 11-7 (1.07g, 2.57mmol) and Boc 2 O (1.19ml, 5.13mmol) in the solution in CH 2 Cl 2 (20ml) in DMAP (157mg, 1.28mmol). After stirring at room temperature for 45 minutes, the reaction mixture was concentrated. The residue was purified by silica gel chromatography to afford compound 11-8 (1.33 g, 2.57 mmol, 100%).

1H-NMR(CDCl3)δ：1.52(s,9H),1.97(s,3H),3.56-3.74(m,2H),4.31(dt,J=30.6,7.6Hz,1H),5.32(d,J=46.9Hz,1H),7.14(m,1H), 7.27(m,1H),7.41(m,1H),7.48(m,1H)。 1 H-NMR (CDCl 3 ) δ: 1.52 (s, 9H), 1.97 (s, 3H), 3.56-3.74 (m, 2H), 4.31 (dt, J = 30.6, 7.6 Hz, 1H), 5.32 (d) , J = 46.9 Hz, 1H), 7.14 (m, 1H), 7.27 (m, 1H), 7.41 (m, 1H), 7.48 (m, 1H).

步驟8 Step 8

在室溫下向化合物11-8(1.33g，2.57mmol)及n-Bu3SnH(1.64ml，6.16mmol)於甲苯(26ml)中之溶液中添加AIBN(63.2mg，385μmol)。在80℃下攪拌1h之後，將反應混合物冷卻至室溫且濃縮。藉由矽膠層析純化殘餘物，獲得化合物11-9(717.1mg1.83mmol，71%)。 A solution of compound 11-8 (1.33 g, 2.57 mmol) and n- Bu 3 SnH (1.64 ml, 6.16 mmol) in toluene (26 ml) was added to AIBN (63.2 mg, 385 μmol). After stirring at 80 ° C for 1 h, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography to afford Compound 11-9 (717.1.

1H-NMR(CDCl3)δ：1.52(s,9H),1.75(t,J=19.8Hz,3H),1.97(s,3H),4.05(ddd,J=30.7,10.4,4.8Hz,1H),5.27(d,J=46.9Hz,1H),7.13(m,1H),7.25(m,1H),7.39(m,1H),7.48(m,1H)。 1 H-NMR (CDCl 3 ) δ: 1.52 (s, 9H), 1.75 (t, J = 19.8 Hz, 3H), 1.97 (s, 3H), 4.05 (ddd, J = 30.7, 10.4, 4.8 Hz, 1H ), 5.27 (d, J = 46.9 Hz, 1H), 7.13 (m, 1H), 7.25 (m, 1H), 7.39 (m, 1H), 7.48 (m, 1H).

步驟9 Step 9

在室溫下向化合物11-9(717.1mg 1.83mmol)於EtOH(12ml)及H2O(6ml)中之溶液中添加Ba(OH)2 8H2O(1.73g，5.50mmol)。在室溫下攪拌1.5h之後，用檸檬酸水溶液淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。用AcOEt及己烷洗滌殘餘物且過濾不溶物質。濃縮濾液且藉由矽膠層析純化殘餘物，獲得化合物11-10(630.1mg，1.73mmol，94%)。 Add a solution of compound 11-9 (717.1mg 1.83mmol) in EtOH the (12ml) and H 2 O (6ml) solution of Ba (OH) 2 8H 2 O (1.73g, 5.50mmol). After stirring at room temperature for 1.5 h, the reaction mixture was quenched with aqueous citric acid. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was washed with AcOEt and hexanes and filtered to dissolve material. The filtrate was concentrated and the residue was purified EtOAcjjjjjjjj

1H-NMR(CDCl3)δ：1.42(s,9H),1.61(t,J=19.3Hz,3H),2.02(s,3H),2.67(dd,J=9.3,3.8Hz,1H),3.62(brs,1H),5.14(d,J=44.5Hz,1H),6.27(brs,1H),7.05(m,1H),7.16(m,1H),7.29(m,1H),7.39(m,1H)。 1 H-NMR (CDCl 3 ) δ: 1.42 (s, 9H), 1.61 (t, J = 19.3 Hz, 3H), 2.02 (s, 3H), 2.67 (dd, J = 9.3, 3.8 Hz, 1H), 3.62 (brs, 1H), 5.14 (d, J = 44.5 Hz, 1H), 6.27 (brs, 1H), 7.05 (m, 1H), 7.16 (m, 1H), 7.29 (m, 1H), 7.39 (m) , 1H).

步驟10 Step 10

在室溫下向化合物11-10(630.1mg，1.73mmol)及於MeOH(6ml)中之溶液中添加HCl-二烷(4M，1.73ml，6.90mmol)。在50℃下攪拌2.5h之後，濃縮反應混合物且用NaHCO3飽和水溶液淬滅。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。獲得之化合物11-11不 經進一步純化即用於下一反應。 Add HCl-II to a solution of compound 11-10 (630.1 mg, 1.73 mmol) in MeOH (6 mL) Alkane (4M, 1.73 ml, 6.90 mmol). After stirring for 2.5h at 50 ℃, the reaction mixture was concentrated and washed with saturated aqueous NaHCO 3 was quenched. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The obtained compound 11-11 was used in the next reaction without further purification.

1H-NMR(CDCl3)δ：1.64(td,J=19.6,1.5Hz,3H),1.76(s,3H),3.46(dt,J=29.9,9.5Hz,1H),5.19(d,J=45.7Hz,1H),7.09(m,1H),7.23(m,1H),7.35(m,1H),7.57(m,1H)。 1 H-NMR (CDCl 3 ) δ: 1.64 (td, J = 19.6, 1.5 Hz, 3H), 1.76 (s, 3H), 3.46 (dt, J = 29.9, 9.5 Hz, 1H), 5.19 (d, J) = 45.7 Hz, 1H), 7.09 (m, 1H), 7.23 (m, 1H), 7.35 (m, 1H), 7.57 (m, 1H).

步驟11 Step 11

在室溫下向化合物11-11於CH2Cl2(3ml)中之溶液中添加BzNCS(348μl，2.59mmol)。在室溫下攪拌2.5h之後，濃縮反應混合物。藉由矽膠層析純化殘餘物，獲得化合物11-12(630.9mg，1.47mmol，85%，2個步驟)。 11-11 to the compound at room temperature to CH 2 Cl 2 (3ml) was added in the BzNCS (348μl, 2.59mmol). After stirring at room temperature for 2.5 h, the reaction mixture was concentrated. The residue was purified by silica gel chromatography to afford compound 11-12 (630.9 mg, 1.47 mmol, 85%, 2 steps).

1H-NMR(CDCl3)δ：1.69(t,J=19.2Hz,3H),2.31(s,3H),2.74(dd,J=9.9,2.9Hz,1H),3.85(m,1H),5.41(d,J=44.4Hz,1H),7.08(m,1H),7.18(m,1H),7.33(m,1H),7.47(m,1H),7.52(m,2H),7.63(m,1H),7.87(m,2H),8.91(s,1H),11.80(s,1H)。 1 H-NMR (CDCl 3 ) δ: 1.69 (t, J = 19.2 Hz, 3H), 2.31 (s, 3H), 2.74 (dd, J = 9.9, 2.9 Hz, 1H), 3.85 (m, 1H), 5.41 (d, J = 44.4 Hz, 1H), 7.08 (m, 1H), 7.18 (m, 1H), 7.33 (m, 1H), 7.47 (m, 1H), 7.52 (m, 2H), 7.63 (m) , 1H), 7.87 (m, 2H), 8.91 (s, 1H), 11.80 (s, 1H).

步驟12 Step 12

在室溫下向化合物11-12(630.9mg，1.47mmol)於CH3CN(12ml)中之溶液中添加WSCD鹽酸鹽(565mg，2.95mmol)。在50℃下攪拌1.5h之後，將反應混合物冷卻至室溫且用H2O淬滅。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物11-13(564.0mg，1.43mmol，97%)。 Was added WSCD hydrochloride (565mg, 2.95mmol) in to the 3 CN (12ml) solution of compound 11-12 (630.9mg, 1.47mmol) in CH at room temperature. After stirring for 1.5h at 50 ℃, the reaction mixture was cooled to room temperature and quenched with H 2 O. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by EtOAc EtOAc (EtOAc)

1H-NMR(CDCl3)δ：1.83(td,J=19.7,1.9Hz,3H),1.89(s,3H),4.11(ddd,J=29.1,10.0,5.0Hz,1H),5.52(d,J=47.2Hz,1H),7.17(m,1H),7.24(m,1H),7.38-7.48(m,4H),7.53(m,1H),8.27(m,2H),11.80(s,1H)。 1 H-NMR (CDCl 3 ) δ: 1.83 (td, J = 19.7, 1.9 Hz, 3H), 1.89 (s, 3H), 4.11 (ddd, J = 29.1, 10.0, 5.0 Hz, 1H), 5.52 (d) , J=47.2 Hz, 1H), 7.17 (m, 1H), 7.24 (m, 1H), 7.38-7.48 (m, 4H), 7.53 (m, 1H), 8.27 (m, 2H), 11.80 (s, 1H).

步驟13 Step 13

在室溫下向化合物11-13(554.0mg，1.40mmol)於MeOH(22ml)中之溶液中添加K2CO3(1.17g，8.43mmol)。在80℃下攪拌3h之後， 將反應混合物冷卻至室溫且用H2O淬滅。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物11-14(374.5mg，1.29mmol，92%)。 Add K 2 CO 3 (1.17g, 8.43mmol ) in the direction (22ml) solution of compound 11-13 (554.0mg, 1.40mmol) in MeOH at room temperature. After stirring for 3h at 80 ℃, the reaction mixture was cooled to room temperature and quenched with H 2 O. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to afford Compound 11-14 (374.5 <RTIgt;

1H-NMR(CDCl3)δ：1.66(s,3H),1.71(t,J=19.7Hz,3H),3.83(ddd,J=30.0,10.8,4.4Hz,1H),4.29(brs,2H),5.35(d,J=48.2Hz,1H),7.05(m,1H),7.17(m,1H),7.29(m,1H),7.44(m,1H)。 1 H-NMR (CDCl 3 ) δ: 1.66 (s, 3H), 1.71 (t, J = 19.7 Hz, 3H), 3.83 (ddd, J = 30.0, 10.8, 4.4 Hz, 1H), 4.29 (brs, 2H) ), 5.35 (d, J = 48.2 Hz, 1H), 7.05 (m, 1H), 7.17 (m, 1H), 7.29 (m, 1H), 7.44 (m, 1H).

步驟14 Step 14

在-20℃下向化合物11-14(360.0mg，1.24mmol)於TFA(4ml)中之溶液中添加H2SO4(1ml)。在0℃下攪拌5分鐘之後，將反應混合物冷卻至-20℃且添加HNO3(83μl，1.86mmol)。在0℃下攪拌15分鐘之後，用K2CO3水溶液淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物11-15(530mg，定量)。 Was added in the TFA (4ml) solution of compound 11-14 (360.0mg, 1.24mmol) at -20 ℃ H 2 SO 4 (1ml ). After stirring at 0 °C for 5 minutes, the reaction mixture was cooled to -20 ° C and HNO 3 (83 μl, 1.86 mmol) was added. After stirring for 15 minutes at 0 ℃, with K 2 CO 3 solution the reaction mixture was quenched. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to afford compound 11-15 (530 mg, quantitative).

1H-NMR(CDCl3)δ：1.77(t,J=19.7Hz,3H),1.87(s,3H),4.05(m,1H),5.46(d,J=46.6Hz,1H),7.34(m,1H),8.27-8.36(m,2H)。 1 H-NMR (CDCl 3 ) δ: 1.77 (t, J = 19.7 Hz, 3H), 1.87 (s, 3H), 4.05 (m, 1H), 5.46 (d, J = 46.6 Hz, 1H), 7.34 ( m, 1H), 8.27-8.36 (m, 2H).

步驟15 Step 15

在室溫下向化合物11-15(530mg，定量)及Boc2O(864μl，3.72mmol)於CH2Cl2(7ml)中之溶液中添加DMAP(182mg，1.49mmol)。 在室溫下攪拌1h之後，濃縮反應混合物。藉由矽膠層析純化殘餘物，獲得化合物11-16(603.8mg，1.13mmol，91%，2個步驟)。 To a solution of compound 11-15 (530mg, quant.) And Boc 2 O (864μl, 3.72mmol) in the 2 Cl 2 (7ml) was added in CH DMAP (182mg, 1.49mmol). After stirring at room temperature for 1 h, the reaction mixture was concentrated. The residue was purified by silica gel chromatography to afford compound 11-16 (603.8mg, 1.13mmol, 91%, 2 steps).

1H-NMR(CDCl3)δ：1.52(s,18H),1.73(s,3H),1.74(m,3H),3.88(ddd,J=28.9,10.3,4.3Hz,1H),5.39(d,J=47.4Hz,1H),7.29(m,1H),8.27(m,1H),8.51(m,1H)。 1 H-NMR (CDCl 3 ) δ: 1.52 (s, 18H), 1.73 (s, 3H), 1.74 (m, 3H), 3.88 (ddd, J = 28.9, 10.3, 4.3 Hz, 1H), 5.39 (d) , J = 47.4 Hz, 1H), 7.29 (m, 1H), 8.27 (m, 1H), 8.51 (m, 1H).

步驟16 Step 16

在室溫下向化合物11-16(603.8mg，1.13mmol)於THF(8ml)及MeOH(4ml)中之溶液中添加Pd/C(60.0mg)。在室溫下在H2氛圍下攪 拌3.5h之後，經由矽藻土(註冊商標)墊過濾反應混合物，且用AcOEt洗滌殘餘物。濃縮濾液，且藉由矽膠層析純化殘餘物，獲得化合物11-17。獲得之化合物11-17藉由自AcOEt/己烷濕磨進一步純化，得到化合物11-17(482.9mg，955μmol，85%)。 To a solution of compound 11-16 (603.8 mg, 1.13 mmol) in THF (8 mL) and MeOH (4 mL). After stirring at room temperature for 3.5 h under H 2 atmosphere, the reaction mixture was filtered through a pad of Celite (registered trademark), and the residue was washed with AcOEt. The filtrate was concentrated, and the residue was purified by silica gel chromatography to afford compound 11-17. The obtained compound 11-17 was further purified by wet-milling from AcOEt/hexane to give compound 11-17 (482.9 mg, 955 μmol, 85%).

1H-NMR(CDCl3)δ：1.52(s,18H),1.69(s,3H),1.72(t,J=19.6Hz,3H),3.56(brs,2H),4.02(m,1H),5.37(d,J=47.8Hz,1H),6.57(m,1H),6.81(m,1H),6.87(m,1H)。 1 H-NMR (CDCl 3) δ: 1.52 (s, 18H), 1.69 (s, 3H), 1.72 (t, J = 19.6Hz, 3H), 3.56 (brs, 2H), 4.02 (m, 1H), 5.37 (d, J = 47.8 Hz, 1H), 6.57 (m, 1H), 6.81 (m, 1H), 6.87 (m, 1H).

步驟17 Step 17

在室溫下向化合物11-17(70.0mg，138μmol)、5-氰基吡啶甲酸水合物(27.6mg，166μmol)及二異丙基乙胺(48μl，277μmol)於DMF(2ml)中之溶液中添加HATU(63.2mg，166μmol)。在室溫下攪拌50分鐘之後，用NH4Cl飽和水溶液淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物11-18(91.6mg，定量)。 To a solution of compound 11-17 (70.0 mg, 138 μmol), 5-cyanopyridinecarboxylic acid hydrate (27.6 mg, 166 μmol) and diisopropylethylamine (48 μl, 277 μmol) in DMF (2 ml) at room temperature HATU (63.2 mg, 166 μmol) was added. After stirring at room temperature for 50 minutes, treated with saturated aqueous NH 4 Cl the reaction mixture was quenched. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to afford compound 11-18 (91.6 mg, quantitative).

1H-NMR(CDCl3)δ：1.56(s,18H),1.73(t,J=19.7Hz,3H),1.76(s,3H),4.01(ddd,J=29.6,10.2,4.4Hz,1H),5.40(d,J=47.6Hz,1H),7.16(m,1H),7.53(m,1H),8.21(d,J=8.2Hz,1H),8.37(m,1H),8.43(d,J=8.2Hz,1H),8.80(s,1H),9.96(s,1H)。 1 H-NMR (CDCl 3 ) δ: 1.56 (s, 18H), 1.73 (t, J = 19.7 Hz, 3H), 1.76 (s, 3H), 4.01 (ddd, J = 29.6, 10.2, 4.4 Hz, 1H ), 5.40 (d, J = 47.6 Hz, 1H), 7.16 (m, 1H), 7.53 (m, 1H), 8.21 (d, J = 8.2 Hz, 1H), 8.37 (m, 1H), 8.43 (d) , J = 8.2 Hz, 1H), 8.80 (s, 1H), 9.96 (s, 1H).

步驟18 Step 18

在室溫下將化合物11-18(91.6mg)溶解於甲酸(1ml，26.1mmol)中。在室溫下攪拌8h之後，用K2CO3水溶液淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。藉由自AcOEt/己烷濕磨純化殘餘物，得到純化合物I-40(52.2mg，120μmol，87%，2個步驟)。 Compound 11-18 (91.6 mg) was dissolved in formic acid (1 mL, 26.1 mmol). After stirring at rt for 8h, with K 2 CO 3 solution the reaction mixture was quenched. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by wet-purified from EtOAc (hexane) to afford purified compound I-40 (52.2 mg, 120.

1H-NMR(CDCl3)δ：1.67(s,3H),1.72(t,J=19.7Hz,3H),3.88(ddd,J=29.9,10.8,4.4Hz,1H),4.33(brs,2H),5.38(d,J=48.1Hz, 1H),7.12(m,1H),7.55(m,1H),8.02(m,1H),8.21(d,J=8.3Hz,1H),8.43(d,J=8.3Hz,1H),8.90(s,1H),9.87(s,1H)。 1 H-NMR (CDCl 3 ) δ: 1.67 (s, 3H), 1.72 (t, J = 19.7 Hz, 3H), 3.88 (ddd, J = 29.9, 10.8, 4.4 Hz, 1H), 4.33 (brs, 2H) ), 5.38 (d, J = 48.1 Hz, 1H), 7.12 (m, 1H), 7.55 (m, 1H), 8.02 (m, 1H), 8.21 (d, J = 8.3 Hz, 1H), 8.43 (d) , J = 8.3 Hz, 1H), 8.90 (s, 1H), 9.87 (s, 1H).

實例12 合成化合物I-82 Example 12 Synthesis of Compound I-82

步驟1 step 1

在室溫下向化合物12-1(1.50g，4.88mmol)及咪唑(798mg，11.7mmol)於DMF(15ml)中之溶液中添加TBSCl(883mg，5.86mmol)。在室溫下攪拌45分鐘之後，用NaHCO3飽和水溶液淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮，獲得化合物12-2。獲得之化合物12-2不經進一步純化即用於下一反應。 TBSCl (883 mg, 5.86 mmol) was added to a solution of Compound 12-1 (1.50 g, 4.88 mmol) After stirring at room temperature for 45 minutes, treated with saturated aqueous NaHCO 3 to quench the reaction mixture. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated to give compound 12-2. The obtained compound 12-2 was used in the next reaction without further purification.

LC/MS(Shimadzu)：RT 2.59,MS計算值422.18(M+H+)，實驗值422.00。 </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI>

步驟2 Step 2

在室溫下向化合物12-2及Boc2O(6.57ml，28.3mmol)於CH2Cl2 (20ml)中之溶液中添加DMAP(238mg，1.95mmol)。在室溫下攪拌1h之後，濃縮反應混合物。藉由矽膠層析純化殘餘物，獲得化合物12-3(2.60g，定量)。 DMAP at room temperature was added a solution of compound 12-2 and Boc 2 O (6.57ml, 28.3mmol) in CH 2 Cl 2 (20ml) in a solution of (238mg, 1.95mmol). After stirring at room temperature for 1 h, the reaction mixture was concentrated. The residue was purified by silica gel chromatography to afford compound 12-3 (2.60 g, quantitative).

1H-NMR(CDCl3)δ：-0.04(s,3H),-0.02(s,3H),0.69(s,9H),1.52(s,9H),1.98(m,3H),3.76(m,1H),3.94(ddd,J=24.1,11.8,6.0Hz,1H),4.34(m,1H),5.38(d,J=46.9Hz,1H),7.09(m,1H),7.23(m,1H),7.36(m,1H),7.48(m,1H)。 1 H-NMR (CDCl 3 ) δ: -0.04 (s, 3H), -0.02 (s, 3H), 0.69 (s, 9H), 1.52 (s, 9H), 1.98 (m, 3H), 3.76 (m) , 1H), 3.94 (ddd, J=24.1, 11.8, 6.0 Hz, 1H), 4.34 (m, 1H), 5.38 (d, J = 46.9 Hz, 1H), 7.09 (m, 1H), 7.23 (m, 1H), 7.36 (m, 1H), 7.48 (m, 1H).

步驟3 Step 3

在室溫下向化合物12-3(2.60g)於MeOH(25ml)中之溶液中添加K2CO3(2.70g，19.5mmol)。在室溫下攪拌45分鐘之後，用NH4Cl飽和水溶液淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮，獲得化合物12-4。獲得之化合物12-4不經進一步純化即用於下一反應。 Add a solution of compound 12-3 (2.60g) in MeOH (25ml) in a solution of K 2 CO 3 (2.70g, 19.5mmol ). After stirring at room temperature for 45 minutes, treated with saturated aqueous NH 4 Cl the reaction mixture was quenched. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated to afford compound 12-4. The obtained compound 12-4 was used in the next reaction without further purification.

LC/MS(Shimadzu)：RT 2.94,MS計算值496.25(M+H+)，實驗值496.25。 LC / MS (Shimadzu): RT 2.94, MS calcd 496.25 (M + H +), Found 496.25.

步驟4 Step 4

在室溫下向化合物12-4於CH2Cl2(50mL)中之溶液中添加TFA(5ml，64.9mmol)。在室溫下攪拌1h之後，用NaHCO3及K2CO3飽和水溶液淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物12-5(1.53g，3.87mmol，79%，4個步驟)。 12-4 To a solution of compound added to CH 2 Cl 2 (50mL) in a solution of TFA (5ml, 64.9mmol). After stirring at room temperature for 1h, washed with saturated aqueous NaHCO 3 K 2 CO 3 and the reaction mixture was quenched. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to afford compound 12-5 (1.

1H-NMR(CDCl3)δ：-0.05(s,3H),-0.02(s,3H),0.74(s,9H),1.74(s,3H),3.61-3.77(m,2H),3.91(ddd,J=23.5,11.5,7.7Hz,1H),5.29(d,J=45.8Hz,1H),7.06(m,1H),7.20(m,1H),7.32(m,1H),7.59(m,1H)。 1 H-NMR (CDCl 3 ) δ: -0.05 (s, 3H), -0.02 (s, 3H), 0.74 (s, 9H), 1.74 (s, 3H), 3.61-3.77 (m, 2H), 3.91 (ddd, J = 23.5, 11.5, 7.7 Hz, 1H), 5.29 (d, J = 45.8 Hz, 1H), 7.06 (m, 1H), 7.20 (m, 1H), 7.32 (m, 1H), 7.59 ( m, 1H).

步驟5 Step 5

在室溫下向化合物12-5(1.53g，3.87mmol)於CH2Cl2(6ml)中之溶液中添加BzNCS(780μl，5.80mmol)。在室溫下攪拌1h之後，濃縮反應混合物。藉由矽膠層析純化殘餘物，獲得化合物12-6(2.07g，包括化合物12-7)。 (, 3.87mmol 1.53g) in the 2 Cl 2 (6ml) was added in CH BzNCS at room temperature a solution of compound 12-5 (780μl, 5.80mmol). After stirring at room temperature for 1 h, the reaction mixture was concentrated. The residue was purified by silica gel chromatography to afford compound 12-6 (2.07 g, Compounds 12-7).

1H-NMR(CDCl3)δ：0.01(s,3H),0.04(s,3H),0.81(s,9H),2.35(brs,3H),3.22(dd,J=11.0,2.5Hz,1H),3.76(td,J=11.8,5.5Hz,1H),3.96-4.15(m,2H),5.38(d,J=44.2Hz,1H),7.06(m,1H),7.16(m,1H),7.31(m,1H),7.48(m,1H),7.52(m,2H),7.63(m,1H),7.86(m,2H),8.89(s,1H),11.92(s,1H)。 1 H-NMR (CDCl 3 ) δ: 0.01 (s, 3H), 0.04 (s, 3H), 0.81 (s, 9H), 2.35 (brs, 3H), 3.22 (dd, J = 11.0, 2.5 Hz, 1H) ), 3.76 (td, J = 11.8, 5.5 Hz, 1H), 3.96-4.15 (m, 2H), 5.38 (d, J = 44.2 Hz, 1H), 7.06 (m, 1H), 7.16 (m, 1H) , 7.31 (m, 1H), 7.48 (m, 1H), 7.52 (m, 2H), 7.63 (m, 1H), 7.86 (m, 2H), 8.89 (s, 1H), 11.92 (s, 1H).

步驟6 Step 6

在室溫下向化合物12-6(2.07g)於CH3CN(21ml)中之溶液中添加WSCD鹽酸鹽(1.42g，7.41mmol)。在50℃下攪拌1.5h之後，將反應混合物冷卻至室溫且用H2O淬滅。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮，獲得化合物12-7。獲得之化合物12-7不經進一步純化即用於下一反應。 Was added WSCD hydrochloride (1.42g, 7.41mmol) in to the 3 CN (21ml) solution of compound 12-6 (2.07g) in CH at room temperature. After stirring for 1.5h at 50 ℃, the reaction mixture was cooled to room temperature and quenched with H 2 O. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated to give compound 12-7. The obtained compound 12-7 was used in the next reaction without further purification.

LC/MS(Shimadzu)：RT 3.06,MS計算值525.22(M+H+)，實驗值525.20。 LC / MS (Shimadzu): RT 3.06, MS calcd 525.22 (M + H +), Found 525.20.

步驟7 Step 7

在室溫下向化合物12-7於THF(20ml)中之溶液中添加TBAF(1M，於THF中，7.41ml，7.41mmol)。在室溫下攪拌10分鐘之後，用NH4Cl飽和水溶液淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物12-8(1.55g，3.78mmol，98%，3個步驟)。 To a solution of compound 12-7 in THF (20 mL), EtOAc (1M, EtOAc. After stirring at room temperature for 10 minutes, treated with saturated aqueous NH 4 Cl the reaction mixture was quenched. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to afford compound 12-8 (1.55 g, 3.78 mmol, 98%, 3 steps).

1H-NMR(CDCl3)δ：1.90(s,3H),3.96(ddd,J=15.7,13.3,7.9Hz,1H),4.14(m,1H),4.35(ddd,J=29.5,12.9,6.4Hz,1H),5.62(d,J=46.9Hz,1H),7.17(m,1H),7.24(m,1H),7.38-7.48(m,4H),7.53(m, 1H),8.24(m,2H),11.77(brs,1H)。 1 H-NMR (CDCl 3 ) δ: 1.90 (s, 3H), 3.96 (ddd, J = 15.7, 13.3, 7.9 Hz, 1H), 4.14 (m, 1H), 4.35 (ddd, J = 29.5, 12.9, 6.4 Hz, 1H), 5.62 (d, J = 46.9 Hz, 1H), 7.17 (m, 1H), 7.24 (m, 1H), 7.38-7.48 (m, 4H), 7.53 (m, 1H), 8.24 ( m, 2H), 11.77 (brs, 1H).

步驟8 Step 8

在室溫下向化合物12-8(500mg，1.22mmol)於CH2Cl2(10ml)中之溶液中添加戴斯-馬丁高碘烷(1.03g，2.44mmol)。在室溫下攪拌1h之後，用NaHCO3及Na2S2O3飽和水溶液淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮，獲得化合物12-9。獲得之化合物12-9不經進一步純化即用於下一反應。 Was added Dess to the compound of 12-8 (500mg, 1.22mmol) in CH 2 Cl 2 (10ml) at room temperature was - Martin periodinane (1.03g, 2.44mmol). After stirring at room temperature for 1h, the reaction mixture was washed with NaHCO 3 and Na 2 S 2 O 3 was quenched with saturated aq. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated to give compound 12-9. The obtained compound 12-9 was used in the next reaction without further purification.

LC/MS(Shimadzu)：RT 1.86,MS計算值427.13(M+H+)，實驗值427.10。 LC / MS (Shimadzu): RT 1.86, MS calcd 427.13 (M + H +), Found 427.10.

步驟9 Step 9

在0℃下向溴化甲基三苯基鏻(1.39g，3.90mmol)於THF(8ml)中之懸浮液中添加KHMDS(0.5M，於甲苯中，7.31ml，3.65mmol)。 在0℃下攪拌20分鐘之後，添加THF(8ml)中之化合物12-9。在室溫下攪拌3h之後，用H2O淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物12-10(255.3mg，628μmol，52%)。 To a suspension of methyltriphenylphosphonium bromide (1.39 g, 3.90 mmol) in THF (8 mL), EtOAc (EtOAc,EtOAc. After stirring at 0 °C for 20 minutes, compound 12-9 in THF (8 mL) was added. After stirring at rt for 3h, quenched with H 2 O the reaction mixture. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to afford compound 12-10 (255.3mg,

1H-NMR(CDCl3)δ：1.88(s,3H),4.18(ddd,J=28.9,9.3,6.0Hz,1H),5.54(d,J=47.2Hz,1H),5.64(d,J=11.0Hz,1H),5.87(m,1H),6.08(m,1H),7.17(m,1H),7.24(m,1H),7.38-7.48(m,4H),7.52(m,1H),8.27(m,2H),11.78(brs,1H)。 1 H-NMR (CDCl 3 ) δ: 1.88 (s, 3H), 4.18 (ddd, J = 28.9, 9.3, 6.0 Hz, 1H), 5.54 (d, J = 47.2 Hz, 1H), 5.64 (d, J) =11.0Hz,1H), 5.87(m,1H),6.08(m,1H),7.17(m,1H), 7.24(m,1H),7.38-7.48(m,4H),7.52(m,1H) , 8.27 (m, 2H), 11.78 (brs, 1H).

步驟10 Step 10

在室溫下向化合物12-10(225.3mg，554μmol)及Boc2O(257μl，1.11mmol)於CH2Cl2(4.6ml)中之溶液中添加DMAP(13.6mg，111μmol)。在室溫下攪拌40分鐘之後，濃縮反應混合物。藉由矽膠層析純化殘餘物，獲得化合物12-11(289.6mg，定量)。 To a solution of the compound 12-10 (225.3 mg, 554 μmol) and Boc 2 O (257 μl, 1.11 mmol) in CH 2 Cl 2 (4.6 ml) was added DMAP (13.6 mg, 111 μmol). After stirring at room temperature for 40 minutes, the reaction mixture was concentrated. The residue was purified by silica gel chromatography to afford compound 12-11 (289.6mg, quantitative).

1H-NMR(CDCl3)δ：1.38(m,3H),1.48(s,9H),4.05(ddd,J=28.6, 9.9,6.3Hz,1H),5.31(d,J=47.8Hz,1H),5.60(d,J=11.0Hz,1H),5.77(m,1H),5.99(m,1H),7.06(m,1H),7.17(m,1H),7.31(m,1H),7.40-7.47(m,3H),7.55(m,1H),7.76(m,2H)。 1 H-NMR (CDCl 3 ) δ: 1.38 (m, 3H), 1.48 (s, 9H), 4.05 (ddd, J = 28.6, 9.9, 6.3 Hz, 1H), 5.31 (d, J = 47.8 Hz, 1H) ), 5.60 (d, J = 11.0 Hz, 1H), 5.77 (m, 1H), 5.99 (m, 1H), 7.06 (m, 1H), 7.17 (m, 1H), 7.31 (m, 1H), 7.40 - 7.47 (m, 3H), 7.55 (m, 1H), 7.76 (m, 2H).

步驟11 Step 11

在試管中，在0℃下向水性NaOH(30%，2ml)及Et2O(6ml)之混合物中添加1-甲基-1-亞硝基脲(571mg，2.77mmol)。在0℃下攪拌20分鐘之後，有機相之顏色變為黃色，其指示能夠製備重氮甲烷之Et2O溶液。在獨立燒瓶中，在0℃下向化合物12-11(289.6mg)及Pd(OAc)2(24.9mg，111μmol)於Et2O(6ml)中之懸浮液中添加重氮甲烷之Et2O溶液。在0℃下攪拌15分鐘之後，用H2O及AcOH淬滅反應混合物。添加NaHCO3飽和水溶液，且用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物12-12(275.7mg，530μmol，96%，2個步驟)。 To a mixture of aqueous NaOH (30%, 2 ml) and Et 2 O (6 ml) was added 1-methyl-1-nitrosourea (571 mg, 2.77 mmol). After stirring at 0 ° C for 20 minutes, the color of the organic phase turned yellow, indicating the ability to prepare a solution of diazomethane in Et 2 O. To a suspension of compound 12-11 (289.6 mg) and Pd(OAc) 2 (24.9 mg, 111 μmol) in Et 2 O (6 ml) was added Et 2 O of diazomethane in a separate flask at 0 ° C. Solution. After stirring at 0 ℃ 15 minutes, treated with H 2 O and the reaction mixture was quenched with AcOH. Saturated aqueous NaHCO 3 was added, and the aqueous phase extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to afford compound 12-12 (275.7 mg, 530.

1H-NMR(CDCl3)δ：0.59-0.78(m,4H),1.33-1.44(m,4H),1.48(s,9H),4.02(ddd,J=28.9,9.5,7.4Hz,1H),5.34(d,J=47.6Hz,1H),7.05(m,1H),7.17(m,1H),7.30(m,1H),7.40-7.49(m,3H),7.54(m,1H),7.79(m,2H)。 1 H-NMR (CDCl 3 ) δ: 0.59-0.78 (m, 4H), 1.33-1.44 (m, 4H), 1.48 (s, 9H), 4.02 (ddd, J = 28.9, 9.5, 7.4 Hz, 1H) , 5.34 (d, J = 47.6 Hz, 1H), 7.05 (m, 1H), 7.17 (m, 1H), 7.30 (m, 1H), 7.40-7.49 (m, 3H), 7.54 (m, 1H), 7.79 (m, 2H).

步驟12 Step 12

在室溫下向化合物12-12(313.6mg，602μmol)於MeOH(3ml)中之溶液中添加K2CO3(416mg，3.01mmol)。在室溫下攪拌40分鐘之後，用H2O淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物12-13(233.1mg，560μmol，93%)。 K 2 CO 3 (416 mg, 3.01 mmol) was added to a solution of compound 12-12 (313.6 mg, 602. After stirring at room temperature for 40 minutes, the reaction was quenched with H 2 O mixture. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to afford compound 12-13 (233.1 mg, 560.

1H-NMR(CDCl3)δ：0.58-0.78(m,4H),1.45(m,1H),1.53(s,9H),1.84(s,3H),4.04(dt,J=29.1,8.0Hz,1H),5.47(d,J=47.2Hz,1H),7.14(m,1H),7.25(m,1H),7.36-7.44(m,2H),10.05(brs,1H)。 1 H-NMR (CDCl 3 ) δ: 0.58-0.78 (m, 4H), 1.45 (m, 1H), 1.53 (s, 9H), 1.84 (s, 3H), 4.04 (dt, J = 29.1, 8.0 Hz , 1H), 5.47 (d, J = 47.2 Hz, 1H), 7.14 (m, 1H), 7.25 (m, 1H), 7.36-7.44 (m, 2H), 10.05 (brs, 1H).

步驟13 Step 13

在室溫下將化合物12-13(233.1mg，560μmol)溶解於TFA(2ml)中。在室溫下攪拌45分鐘之後，將反應混合物冷卻至-20℃且添加H2SO4(0.5ml)。在0℃下攪拌5分鐘之後，將反應混合物冷卻至-20℃且添加HNO3(75μl，1.68mmol)。在0℃下攪拌50分鐘之後，用K2CO3水溶液淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮，獲得化合物12-14(326.3mg，定量)。獲得之化合物12-14不經進一步純化即用於下一反應。 Compound 12-13 (233.1 mg, 560 μmol) was dissolved in TFA (2 mL) at room temperature. After stirring at room temperature for 45 minutes, the reaction mixture was cooled to -20 ° C and H 2 SO 4 (0.5 ml) After stirring at 0 °C for 5 minutes, the reaction mixture was cooled to -20 ° C and HNO 3 (75 μl, 1.68 mmol) was added. After stirring at 0 ℃ 50 minutes, treated with K 2 CO 3 solution the reaction mixture was quenched. The aqueous phase was extracted with AcOEt. Dried over Na 2 SO 4, and the organic layer was concentrated to afford compound 12-14 (326.3mg, quantitative). The obtained compound 12-14 was used in the next reaction without further purification.

1H-NMR(CDCl3)δ：0.60-0.78(m,4H),1.39(m,1H),1.69(s,3H),3.85(ddd,J=29.6,9.2,7.4Hz,1H),5.41(d,J=47.4Hz,1H),7.25(dd,J=10.7,8.9Hz,1H),8.23(ddd,J=8.9,4.1,2.9Hz,1H),8.45(dd,J=6.7,2.9Hz,1H)。 1 H-NMR (CDCl 3 ) δ: 0.60-0.78 (m, 4H), 1.39 (m, 1H), 1.69 (s, 3H), 3.85 (ddd, J = 29.6, 9.2, 7.4 Hz, 1H), 5.41 (d, J = 47.4 Hz, 1H), 7.25 (dd, J = 10.7, 8.9 Hz, 1H), 8.23 (ddd, J = 8.9, 4.1, 2.9 Hz, 1H), 8.45 (dd, J = 6.7, 2.9 Hz, 1H).

步驟14 Step 14

在室溫下向化合物12-14(326.3mg，定量)及Boc2O(325μl，1.40mmol)於CH2Cl2(6ml)中之溶液中添加DMAP(103mg，840μmol)。在室溫下攪拌40分鐘之後，濃縮反應混合物。藉由矽膠層析純化殘餘物，獲得化合物12-15(276.1mg，492μmol，88%，2個步驟)。 DMAP at rt was added a solution of compound 12-14 (326.3mg, quant.) And Boc 2 O (325μl, 1.40mmol) in CH 2 Cl 2 (6ml) in a solution of (103mg, 840μmol). After stirring at room temperature for 40 minutes, the reaction mixture was concentrated. The residue was purified by silica gel chromatography to afford compound 12-15 (276.1 mg, 492.

1H-NMR(CDCl3)δ：0.59-0.80(m,4H),1.40(m,1H),1.52(s,18H),1.74(m,3H),3.93(ddd,J=28.6,8.9,7.0Hz,1H),5.44(d,J=47.2Hz,1H),7.29(dd,J=10.8,9.0Hz,1H),8.27(ddd,J=9.0,4.2,2.9Hz,1H),8.53(dd,J=6.7,2.9Hz,1H)。 1 H-NMR (CDCl 3 ) δ: 0.59-0.80 (m, 4H), 1.40 (m, 1H), 1.52 (s, 18H), 1.74 (m, 3H), 3.93 (ddd, J = 28.6, 8.9, 7.0 Hz, 1H), 5.44 (d, J = 47.2 Hz, 1H), 7.29 (dd, J = 10.8, 9.0 Hz, 1H), 8.27 (ddd, J = 9.0, 4.2, 2.9 Hz, 1H), 8.53 ( Dd, J = 6.7, 2.9 Hz, 1H).

步驟15 Step 15

在室溫下向化合物12-15(276.1mg，492μmol)於THF(3ml)及MeOH(1.5ml)中之溶液中添加Pd/C(52.4mg)。在室溫下在H2氛圍下攪拌6.5h之後，經由矽藻土(註冊商標)墊過濾反應混合物，且用AcOEt洗滌殘餘物。濃縮濾液，且藉由矽膠層析純化殘餘物，獲得化 合物12-16(240.9mg，453μmol，92%)。 To a solution of the compound 12-15 (276.1 mg, 492 μmol) in THF (3 ml) and MeOH (1.5 ml) was added Pd/C (52.4 mg). After stirring at room temperature for 6.5 h under H 2 atmosphere, the reaction mixture was filtered through a pad of Celite (trademark), and the residue was washed with AcOEt. The filtrate was concentrated, and the residue was purifiedjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

1H-NMR(CDCl3)δ：0.58-0.77(m,4H),1.39(m,1H),1.52(s,18H),1.71(m,3H),3.57(brs,2H),4.07(ddd,J=28.7,9.7,6.9Hz,1H),5.43(d,J=47.7Hz,1H),6.57(ddd,J=8.7,3.8,3.0Hz,1H),6.83(dd,J=6.5,3.0Hz,1H),6.87(dd,J=11.7,8.7Hz,1H)。 1 H-NMR (CDCl 3 ) δ: 0.58-0.77 (m, 4H), 1.39 (m, 1H), 1.52 (s, 18H), 1.71 (m, 3H), 3.57 (brs, 2H), 4.07 (ddd , J = 28.7, 9.7, 6.9 Hz, 1H), 5.43 (d, J = 47.7 Hz, 1H), 6.57 (ddd, J = 8.7, 3.8, 3.0 Hz, 1H), 6.83 (dd, J = 6.5, 3.0 Hz, 1H), 6.87 (dd, J = 11.7, 8.7 Hz, 1H).

步驟16 Step 16

在室溫下向化合物12-16(70.0mg，132μmol)、5-(氟甲氧基)吡-2-甲酸(27.2mg，158μmol)及二異丙基乙胺(46μl，263μmol)於DMF(2ml)中之溶液中添加HATU(60.1mg，158μmol)。在室溫下攪拌50分鐘之後，用NH4Cl飽和水溶液淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。藉由矽膠層析純化殘餘物，獲得化合物12-17(86.6mg，126μmol，96%)。 To compound 12-16 (70.0 mg, 132 μmol), 5-(fluoromethoxy)pyrazole at room temperature HATU (60.1 mg, 158 μmol) was added to a solution of 2-carboxylic acid (27.2 mg, 158 μmol) and diisopropylethylamine (46 μl, 263 μmol) in DMF (2 mL). After stirring at room temperature for 50 minutes, treated with saturated aqueous NH 4 Cl the reaction mixture was quenched. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography to afford compound 12-17 (86.6 mg, 126.

1H-NMR(CDCl3)δ：0.59-0.77(m,4H),1.38(m,1H),1.54(s,18H),1.76(m,3H),4.05(m,1H),5.45(d,J=47.4Hz,1H),6.15(ddd,J=50.9,11.5,2.0Hz,2H),7.15(dd,J=11.5,8.8Hz,1H),7.48(dd,J=6.8,2.8Hz,1H),8.20(d,J=1.5Hz,1H),8.37(ddd,J=8.8,4.0,2.8Hz,1H),9.08(d,J=1.5Hz,1H),9.63(s,1H)。 1 H-NMR (CDCl 3 ) δ: 0.59-0.77 (m, 4H), 1.38 (m, 1H), 1.54 (s, 18H), 1.76 (m, 3H), 4.05 (m, 1H), 5.45 (d) , J=47.4 Hz, 1H), 6.15 (ddd, J=50.9, 11.5, 2.0 Hz, 2H), 7.15 (dd, J=11.5, 8.8 Hz, 1H), 7.48 (dd, J=6.8, 2.8 Hz, 1H), 8.20 (d, J = 1.5 Hz, 1H), 8.37 (ddd, J = 8.8, 4.0, 2.8 Hz, 1H), 9.08 (d, J = 1.5 Hz, 1H), 9.63 (s, 1H).

步驟17 Step 17

在室溫下將化合物12-17(86.6mg，126μmol)溶解於甲酸(1ml，26.1mmol)中。在室溫下攪拌15h之後，用K2CO3水溶液淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮。藉由自己烷濕磨純化殘餘物，得到純化合物I-82(52.8mg，109μmol，86%)。 Compound 12-17 (86.6 mg, 126 μmol) was dissolved in formic acid (1 mL, 26.1 mmol) at room temperature. After stirring for 15h at room temperature with K 2 CO 3 solution the reaction mixture was quenched. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by trituration with hexanes to afford purified compound I-82 (52.8 mg, 109.

1H-NMR(CDCl3)δ：0.64(m,2H),0.73(m,2H),1.38(m,1H),1.67(s,3H),3.95(ddd,J=29.9,10.0,7.3Hz,1H),4.37(brs,2H),5.45(d,J=48.1Hz,1H),6.15(m,2H),7.11(dd,J=11.3,8.9Hz,1H),7.50(dd,J=6.8,2.8Hz,1H),8.03(ddd,J=8.9,4.1,2.8Hz,1H),8.29(d,J=1.4 Hz,1H),9.08(d,J=1.4Hz,1H),9.52(s,1H)。 1 H-NMR (CDCl 3 ) δ: 0.64 (m, 2H), 0.73 (m, 2H), 1.38 (m, 1H), 1.67 (s, 3H), 3.95 (ddd, J = 29.9, 10.0, 7.3 Hz , 1H), 4.37 (brs, 2H), 5.45 (d, J = 48.1 Hz, 1H), 6.15 (m, 2H), 7.11 (dd, J = 11.3, 8.9 Hz, 1H), 7.50 (dd, J = 6.8, 2.8 Hz, 1H), 8.03 (ddd, J = 8.9, 4.1, 2.8 Hz, 1H), 8.29 (d, J = 1.4 Hz, 1H), 9.08 (d, J = 1.4 Hz, 1H), 9.52 ( s, 1H).

實例13 合成化合物I-109 Example 13 Synthesis of Compound I-109

步驟1 step 1

在室溫下攪拌化合物3-4(1.25g，2.57mmol)及四氟硼酸銀(I)(1.00g，5.14mmol)於DMSO(6.3mL)及水(0.63mL)中之溶液3.5h。用碳酸氫鈉飽和溶液淬滅反應物。經矽藻土(註冊商標)墊過濾所得混合物且用乙酸乙酯萃取濾液。用水洗滌經合併之有機層且蒸發。藉由急驟管柱層析(矽膠，2：1己烷：乙酸乙酯)純化粗產物，得到呈無色非晶形形式之化合物13-1(560mg，58%)。 A solution of compound 3-4 (1.25 g, 2.57 mmol) and silver (I) tetrafluoroborate (1.00 g, 5.14 mmol) in DMSO (6.3 mL) and water (0.63 mL). The reaction was quenched with a saturated solution of sodium bicarbonate. The resulting mixture was filtered through a pad of celite (registered trademark) and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with water and evaporated. The crude product was purified by flash column chromatography eluting elut elut elut elut elut elut

1H NMR(400MHz,CDCl3)δ：1.89(s,3H),3.17-3.29(m,1H),3.80(dd,J=10.8,7.9Hz,1H),4.04(dd,J=10.8,7.2Hz,1H),5.60(dd,J=47.3,1.6Hz,1H),7.12(dd,J=12.2,8.2Hz,1H),7.20(t,J= 7.7Hz,1H),7.35-7.54(m,5H),8.23(d,J=7.3Hz,2H)。 1 H NMR (400MHz, CDCl 3 ) δ: 1.89 (s, 3H), 3.17-3.29 (m, 1H), 3.80 (dd, J = 10.8,7.9Hz, 1H), 4.04 (dd, J = 10.8,7.2 Hz, 1H), 5.60 (dd, J = 47.3, 1.6 Hz, 1H), 7.12 (dd, J = 12.2, 8.2 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.35-7.54 (m) , 5H), 8.23 (d, J = 7.3 Hz, 2H).

步驟2 Step 2

在0℃下向化合物13-1(560mg，0.84mmol)及氫化鈉(179mg，4.46mmol，60%，於油中)於THF(6mL)中之攪拌懸浮液中添加碘甲烷(0.465mL，7.44mmol)。在0℃下攪拌2h之後，用氯化銨飽和溶液淬滅反應物。用乙酸乙酯萃取混合物且用水洗滌合併之有機層。蒸發溶劑且藉由急驟管柱層析(矽膠，4：1至3：1己烷：乙酸乙酯之梯度)純化粗產物，得到呈無色非晶形形式之化合物13-2(326g，56%)。 Methyl iodide (0.465 mL, 7.44) was added to a stirred suspension of compound 13-1 (560 mg, 0.84 mmol) and sodium hydride (179 mg, 4.46 mmol, 60% in oil) Mm). After stirring at 0 °C for 2 h, the reaction was quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate and the combined organic layers were washed with water. The solvent was evaporated and the crude was purified by flash chromatography eluting elut elut elut elut elut elut .

1H NMR(400MHz,CDCl3)δ：1.88(s,3H),3.21-3.33(m,1H),3.35(s,3H),3.44-3.48(m,1H),3.81(dd,J=9.3,7.3Hz,1H),5.52(dd,J=47.2,2.0Hz,1H),7.12(dd,J=12.3,8.0Hz,1H),7.19(td,J=7.6,1.2Hz,1H),7.34-7.53(m,5H),8.23(d,J=7.0Hz,2H)。 1 H NMR (400MHz, CDCl 3 ) δ: 1.88 (s, 3H), 3.21-3.33 (m, 1H), 3.35 (s, 3H), 3.44-3.48 (m, 1H), 3.81 (dd, J = 9.3 , 7.3 Hz, 1H), 5.52 (dd, J = 47.2, 2.0 Hz, 1H), 7.12 (dd, J = 12.3, 8.0 Hz, 1H), 7.19 (td, J = 7.6, 1.2 Hz, 1H), 7.34 -7.53 (m, 5H), 8.23 (d, J = 7.0 Hz, 2H).

步驟3 Step 3

在室溫下攪拌化合物13-2(326mg，0.84mmol)及單水合肼(0.405mL，8.35mmol)於乙醇(5mL)中之溶液18h。蒸發混合物，且藉由急驟管柱層析(胺基矽膠，1：1己烷：乙酸乙酯)純化粗產物，得到呈無色膠狀物狀之化合物13-3(210mg，88%)。 A solution of compound 13-2 (326 mg, 0.84 mmol) and hydrazine monohydrate (0.405 mL, 8.35 mmol) in ethanol (5 mL). The mixture was evaporated, and the title compound mjjjjjjjjjj

1H NMR(400MHz,CDCl3)δ：1.75(t,J=1.5Hz,3H),3.21-3.33(m,1H),3.32(s,3H),3.40-3.44(m,1H),3.77(dd,J=9.4,6.7Hz,1H),5.33(dd,J=47.7,1.8Hz,1H),7.03(ddd,J=12.4,8.2,1.3Hz,1H),7.12(td,J=7.5,1.3Hz,1H),7.23-7.30(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ: 1.75 (t, J = 1.5Hz, 3H), 3.21-3.33 (m, 1H), 3.32 (s, 3H), 3.40-3.44 (m, 1H), 3.77 ( Dd, J = 9.4, 6.7 Hz, 1H), 5.33 (dd, J = 47.7, 1.8 Hz, 1H), 7.03 (ddd, J = 12.4, 8.2, 1.3 Hz, 1H), 7.12 (td, J = 7.5, 1.3 Hz, 1H), 7.23-7.30 (m, 2H).

步驟4 Step 4

在-20℃下向化合物13-3(210mg，0.73mmol)及硫酸(0.520mL，9.76mmol)於三氟乙酸(2.1mL)中之攪拌懸浮液中添加硝酸(0.049mL，1.10mmol)。在-20℃與-10℃之間攪拌30分鐘之後，用碳酸鉀溶液淬滅反應物。用乙酸乙酯萃取混合物，且用水洗滌合併之有機層。 蒸發溶劑，得到粗產物形式之化合物13-4(231mg)，其不經進一步純化即用於下一反應。 To a stirred suspension of compound 13-3 (210 mg, 0.73 mmol) After stirring at -20 ° C and -10 ° C for 30 minutes, the reaction was quenched with potassium carbonate solution. The mixture was extracted with ethyl acetate and the combined organic layers were washed with water. Evaporation of the solvent gave EtOAc (EtOAc m.

步驟5 Step 5

在80℃下攪拌化合物13-4(231mg)、鐵(311mg，5.58mmol)及氯化銨(447mg，8.37mmol)於甲苯(2mL)及水(2mL)中之懸浮液2h。在冷卻至室溫之後，用碳酸鉀溶液淬滅反應物。經矽藻土(註冊商標)墊過濾混合物，且用乙酸乙酯萃取濾液。用水洗滌合併之有機層且蒸發，得到呈粗產物形式之化合物13-5(206mg)，其不經進一步純化即用於下一反應。 A suspension of compound 13-4 (231 mg), iron (311 mg, 5.58 mmol) and ammonium chloride (447 mg, 8.37 mmol) in toluene (2 mL) and water (2 mL) was stirred for 2h. After cooling to room temperature, the reaction was quenched with potassium carbonate solution. The mixture was filtered through a pad of Celite (registered trademark), and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with EtOAc EtOAc m.

步驟6 Step 6

在-78℃下向化合物13-5(55.6mg)於二氯甲烷(1.1mL)中之攪拌溶液中添加三溴化硼(0.922mL，0.922mmol，二氯甲烷中之1mol/L)。在0℃下攪拌3h之後，在-78℃下將三溴化硼(0.553mL，0.553mmol)添加至混合物中。在0℃下攪拌1h之後，用碳酸氫鈉飽和溶液淬滅反應物。用乙酸乙酯萃取混合物，且用水洗滌合併之有機層。蒸發溶劑，得到粗產物形式之化合物13-6(58.1mg)，其不經進一步純化即用於下一反應。 Boron tribromide (0.922 mL, 0.922 mmol, 1 mol/L in dichloromethane) was added to a stirred solution of Compound 13-5 (55.6 mg) in dichloromethane (1.1 mL). After stirring at 0 ° C for 3 h, boron tribromide (0.553 mL, 0.553 mmol) was added to the mixture at -78 °C. After stirring at 0 °C for 1 h, the reaction was quenched with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate and the combined organic layers were washed with water. The solvent was evaporated to give the title compound m.

步驟7 Step 7

在室溫下向化合物13-6(58.1mg)及氯化氫(0.092mL，0.184mmol，2mol/L，於水中)之攪拌溶液中添加5-(氟甲氧基)吡-2-甲酸(31.7mg，0.184mmol)及WSCD(38.9mg，0.203mmol)。在室溫下攪拌45分鐘之後，用碳酸氫鈉飽和溶液淬滅反應物。用乙酸乙酯萃取混合物。用鹽水洗滌經合併之有機層，經硫酸鈉乾燥且過濾。蒸發溶劑，且用己烷濕磨粗產物，得到I-109(64.5mg，74%，經4個步驟)。 Add 5-(fluoromethoxy)pyridin to a stirred solution of compound 13-6 (58.1 mg) and hydrogen chloride (0.092 mL, 0.184 mmol, 2 mol/L in water) at room temperature 2-carboxylic acid (31.7 mg, 0.184 mmol) and WSCD (38.9 mg, 0.203 mmol). After stirring at room temperature for 45 minutes, the reaction was quenched with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was evaporated, and the crude material was crystallised from EtOAc (EtOAc)

1H NMR(400MHz,CDCl3)δ：1.77(s,3H),3.23-3.35(m,1H),3.75(dd,J=11.0,7.3Hz,1H),4.00(dd,J=11.0,7.3Hz,1H),5.44(d, J=46.7Hz,1H),6.15(d,J=50.2Hz,2H),7.09(dd,J=11.5,8.8Hz,1H),7.34(dd,J=6.7,2.9Hz,1H),7.95-7.99(m,1H),8.30(s,1H),9.08(s,1H),9.48(s,1H)。 1 H NMR (400MHz, CDCl 3 ) δ: 1.77 (s, 3H), 3.23-3.35 (m, 1H), 3.75 (dd, J = 11.0,7.3Hz, 1H), 4.00 (dd, J = 11.0,7.3 Hz, 1H), 5.44 (d, J = 46.7 Hz, 1H), 6.15 (d, J = 50.2 Hz, 2H), 7.09 (dd, J = 11.5, 8.8 Hz, 1H), 7.34 (dd, J = 6.7) , 2.9 Hz, 1H), 7.95-7.99 (m, 1H), 8.30 (s, 1H), 9.08 (s, 1H), 9.48 (s, 1H).

實例14 合成化合物I-94 Example 14 Synthesis of Compound I-94

步驟1 step 1

在室溫下向化合物14-1(537.7mg，1.29mmol)於二甲基乙醯胺(2.5ml)及H2O(2.5ml)中之懸浮液中添加鋅(421mg，6.45mmol)。在80℃下攪拌2h之後，將反應混合物冷卻至0℃且用Na2S2O3水溶液淬滅。經由矽藻土(註冊商標)墊過濾所得混合物，且用AcOEt洗滌殘餘物。用AcOEt萃取水相。經Na2SO4乾燥有機相且濃縮，獲得化合物14-2。獲得之化合物14-2不經進一步純化即用於下一反應。 In dimethylacetamide (2.5ml) and in the H 2 O (2.5ml), was added to the zinc compound 14-1 (537.7mg, 1.29mmol) at room temperature (421mg, 6.45mmol). After stirring for 2h at 80 ℃, the reaction mixture was cooled to 0 ℃ and treated with Na 2 S 2 O 3 aq quenched. The resulting mixture was filtered through a pad of diatomaceous earth (registered trademark), and the residue was washed with AcOEt. The aqueous phase was extracted with AcOEt. The organic phase was dried over Na 2 SO 4 and concentrated to give compound 14-2. The obtained compound 14-2 was used in the next reaction without further purification.

1H-NMR(CDCl3)δ：1.80(s,3H),4.45(d,J=28.2Hz,1H),4.91(ddd,J=17.8,3.9,1.3Hz,1H),5.00(ddd,J=14.8,3.9,1.3Hz,1H),5.29(d,J=46.6Hz,1H),6.02(s,1H),7.15(m,1H),7.27(m,1H),7.41(m,1H),7.53(m,1H)。 1 H-NMR (CDCl 3 ) δ: 1.80 (s, 3H), 4.45 (d, J = 28.2 Hz, 1H), 4.91 (ddd, J = 17.8, 3.9, 1.3 Hz, 1H), 5.00 (ddd, J =14.8, 3.9, 1.3 Hz, 1H), 5.29 (d, J = 46.6 Hz, 1H), 6.02 (s, 1H), 7.15 (m, 1H), 7.27 (m, 1H), 7.41 (m, 1H) , 7.53 (m, 1H).

步驟2 Step 2

在室溫下向化合物14-2及Boc2O(748μl，3.22mmol)於CH2Cl2(3.5ml)中之溶液中添加DMAP(79mg，645μmol)。在室溫下攪拌1.5h之後，濃縮反應混合物。藉由矽膠層析純化殘餘物，獲得化合物14-3(436.3mg，1.17mmol，91%，2個步驟)。 To a solution of the compound 14-2 and Boc 2 O (748 μl, 3.22 mmol) in CH 2 Cl 2 (3.5 ml) was added DMF (79 mg, 645 μmol). After stirring at room temperature for 1.5 h, the reaction mixture was concentrated. The residue was purified by silica gel chromatography to afford compound 14-3 (436.3 mg, 1.17 mmol, 91%, 2 steps).

1H-NMR(CDCl3)δ：1.52(s,9H),1.97(m,3H),4.46(d,J=29.3 Hz,1H),4.91(ddd,J=20.2,4.0,1.3Hz,1H),4.99(ddd,J=12.3,4.0,1.3Hz,1H),5.21(d,J=46.3Hz,1H),7.13(m,1H),7.25(m,1H),7.39(m,1H),7.50(m,1H)。 1 H-NMR (CDCl 3) δ: 1.52 (s, 9H), 1.97 (m, 3H), 4.46 (d, J = 29.3 Hz, 1H), 4.91 (ddd, J = 20.2,4.0,1.3Hz, 1H ), 4.99 (ddd, J = 12.3, 4.0, 1.3 Hz, 1H), 5.21 (d, J = 46.3 Hz, 1H), 7.13 (m, 1H), 7.25 (m, 1H), 7.39 (m, 1H) , 7.50 (m, 1H).

步驟3 Step 3

在室溫下向化合物14-3(456.3mg，1.23mmol)於MeOH(5ml)中之溶液中添加K2CO3(679mg，4.91mmol)。在室溫下攪拌15分鐘之後，用NH4Cl飽和水溶液淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機層且濃縮，獲得化合物14-4。獲得之化合物14-4不經進一步純化即用於下一反應。 K is added to the medium (5ml) solution of compound 14-3 (456.3mg, 1.23mmol) in MeOH at room temperature for 2 CO 3 (679mg, 4.91mmol) . After stirring at room temperature for 15 minutes, treated with saturated aqueous NH 4 Cl the reaction mixture was quenched. The aqueous phase was extracted with AcOEt. The organic layer was dried over Na 2 SO 4 and concentrated to give compound 14-4. The obtained compound 14-4 was used in the next reaction without further purification.

LC/MS(Shimadzu)：RT 2.15,MS計算值346.16(M+H+)，實驗值346.15。 </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI>

步驟4 Step 4

在室溫下向化合物14-4於CH2Cl2(5ml)中之溶液中添加TFA(1ml，13.0mmol)。在室溫下攪拌1h之後，用NaHCO3及K2CO3飽和水溶液淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機相且濃縮。藉由矽膠層析純化殘餘物，獲得化合物14-5(254.6mg，1.04mmol，84%，2個步驟)。 14-4 To a solution of compound added to CH 2 Cl 2 (5ml) in a solution of TFA (1ml, 13.0mmol). After stirring at room temperature for 1h, washed with saturated aqueous NaHCO 3 K 2 CO 3 and the reaction mixture was quenched. The aqueous phase was extracted with AcOEt. Dried over Na 2 SO 4, and the organic phase was concentrated. The residue was purified by silica gel chromatography to afford compound 14-5 (254.6 g, 1.04 mmol, 84%, 2 steps).

1H-NMR(CDCl3)δ：1.77(s,3H),3.89(d,J=31.0Hz,1H),4.71(ddd,J=22.2,2.9,1.4Hz,1H),4.79(ddd,J=10.9,2.9,1.4Hz,1H),5.09(dd,J=44.9,1.1Hz,1H),7.10(m,1H),7.22(m,1H),7.35(m,1H),7.58(m,1H)。 1 H-NMR (CDCl 3 ) δ: 1.77 (s, 3H), 3.89 (d, J = 31.0 Hz, 1H), 4.71 (ddd, J = 22.2, 2.9, 1.4 Hz, 1H), 4.79 (ddd, J = 10.9, 2.9, 1.4 Hz, 1H), 5.09 (dd, J = 44.9, 1.1 Hz, 1H), 7.10 (m, 1H), 7.22 (m, 1H), 7.35 (m, 1H), 7.58 (m, 1H).

步驟5 Step 5

在室溫下向化合物14-5(254.6mg，1.04mmol)於CH2Cl2(2.5ml)中之溶液中添加BzNCS(209μl，1.56mmol)。在室溫下攪拌2.5h之後，濃縮反應混合物。藉由矽膠層析純化殘餘物，獲得化合物14-6(375.5mg，919μmol，89%)。 Add a solution of compound 14-5 (254.6mg, 1.04mmol) in the solution in CH 2 Cl 2 (2.5ml) in BzNCS (209μl, 1.56mmol). After stirring at room temperature for 2.5 h, the reaction mixture was concentrated. The residue was purified by silica gel chromatography to afford compound 14-6 (375.5mg, 919.

1H-NMR(CDCl3)δ：2.30(s,3H),2.56(d,J=9.5Hz,1H),4.36(ddd,J=25.2,9.5,5.0Hz,1H),4.76(dd,J=48.9,3.5Hz,1H),4.85(dd,J=17.7,3.5Hz,1H),5.37(d,J=43.9Hz,1H),7.08(m,1H),7.18(m,1H),7.33(m,1H),7.46-7.56(m,3H),7.63(m,1H),7.87(m,2H),8.89(s,1H),11.85(s,1H)。 1 H-NMR (CDCl 3 ) δ: 2.30 (s, 3H), 2.56 (d, J = 9.5 Hz, 1H), 4.36 (ddd, J = 25.2, 9.5, 5.0 Hz, 1H), 4.76 (dd, J =48.9, 3.5 Hz, 1H), 4.85 (dd, J = 17.7, 3.5 Hz, 1H), 5.37 (d, J = 43.9 Hz, 1H), 7.08 (m, 1H), 7.18 (m, 1H), 7.33 (m, 1H), 7.46-7.56 (m, 3H), 7.63 (m, 1H), 7.87 (m, 2H), 8.89 (s, 1H), 11.85 (s, 1H).

步驟6 Step 6

在室溫下向化合物14-6(375.5mg，919μmol)於CH3CN(7ml)中之溶液中添加WSCD鹽酸鹽(352mg，1.84mmol)。在50℃下攪拌1h之後，將反應混合物冷卻至室溫且用H2O淬滅。用AcOEt萃取水相。 經Na2SO4乾燥有機相且濃縮，獲得化合物14-7。獲得之化合物14-7不經進一步純化即用於下一反應。 Was added WSCD hydrochloride (352mg, 1.84mmol) in the direction (375.5mg, 919μmol) in CH 3 CN (7ml) solution of the compound 14-6 at room temperature. After stirring at 50 ℃ 1h, the reaction mixture was cooled to room temperature and quenched with H 2 O. The aqueous phase was extracted with AcOEt. Dried over Na 2 SO 4, and the organic phase was concentrated to give compound 14-7. The obtained compound 14-7 was used in the next reaction without further purification.

1H-NMR(CDCl3)δ：1.91(s,3H),4.52(d,J=27.7Hz,1H),5.01(dd,J=9.0,4.0Hz,1H),5.09(dd,J=23.7,4.0Hz,1H),5.43(d,J=46.4Hz,1H),7.17(m,1H),7.24(m,1H),7.38-7.49(m,4H),7.53(m,1H),8.27(m,2H),11.81(s,1H)。 1 H-NMR (CDCl 3 ) δ: 1.91 (s, 3H), 4.52 (d, J = 27.7 Hz, 1H), 5.01 (dd, J = 9.0, 4.0 Hz, 1H), 5.09 (dd, J = 23.7) , 4.0 Hz, 1H), 5.43 (d, J = 46.4 Hz, 1H), 7.17 (m, 1H), 7.24 (m, 1H), 7.38-7.49 (m, 4H), 7.53 (m, 1H), 8.27 (m, 2H), 11.81 (s, 1H).

步驟7 Step 7

在室溫下向化合物14-7及Boc2O(427μl，1.84mmol)於CH2Cl2(3.5ml)中之溶液中添加DMAP(22.5mg，184μmol)。在室溫下攪拌30分鐘之後，濃縮反應混合物。藉由矽膠層析純化殘餘物，獲得化合物14-8(416.5mg，878μmol，95%)。 DMAP (22.5 mg, 184 μmol) was added to a solution of compound 14-7 and Boc 2 O (427 μl, 1.84 mmol) in CH 2 Cl 2 (3.5 ml). After stirring at room temperature for 30 minutes, the reaction mixture was concentrated. The residue was purified by silica gel chromatography to afford compound 14-8 (416.5 mg, </RTI>

1H-NMR(CDCl3)δ：1.47(s,9H),1.55(s,3H),4.40(dd,J=27.5,2.8Hz,1H),4.80(dd,J=49.4,3.6Hz,1H),4.95(dd,J=17.8,3.6Hz,1H),5.23(d,J=47.2Hz,1H),7.06(m,1H),7.17(m,1H),7.30(m,1H),7.41-7.53(m,3H),7.55(m,1H),7.78(m,2H)。 1 H-NMR (CDCl 3 ) δ: 1.47 (s, 9H), 1.55 (s, 3H), 4.40 (dd, J = 27.5, 2.8 Hz, 1H), 4.80 (dd, J = 49.4, 3.6 Hz, 1H) ), 4.95 (dd, J = 17.8, 3.6 Hz, 1H), 5.23 (d, J = 47.2 Hz, 1H), 7.06 (m, 1H), 7.17 (m, 1H), 7.30 (m, 1H), 7.41 -7.53 (m, 3H), 7.55 (m, 1H), 7.78 (m, 2H).

步驟8 Step 8

在試管中，在0℃下向水性NaOH(30%，4ml)及Et2O(4ml)之混 合物中添加1-甲基-1-亞硝基脲(905mg，4.39mmol，5當量)。在0℃下攪拌20分鐘之後，有機相之顏色變為黃色，其指示能夠製備重氮甲烷之Et2O溶液。在獨立燒瓶中，在-30℃下向化合物14-8(416.5mg，878μmol)及Pd(OAc)2(39.4mg，176μmol，0.2當量)於Et2O(4ml)中之懸浮液中添加重氮甲烷之Et2O溶液。在-20℃下攪拌反應混合物，且將上文製備之重氮甲烷之Et2O溶液(5×5當量)及Pd(OAc)2(0.2×2當量)以若干批次添加直至化合物14-8完全耗盡。在從第一次添加重氮甲烷溶液起在-20℃下攪拌3h之後，用H2O及AcOH淬滅反應混合物。 添加NaHCO3飽和水溶液且經由矽藻土(註冊商標)墊過濾所得混合物。用AcOEt洗滌濾液。用AcOEt萃取水相。經Na2SO4乾燥有機相且濃縮。藉由矽膠層析純化殘餘物，獲得化合物14-9(259.2mg，531μmol，60%)。 In a test tube, was added 1-methyl-1-nitrosourea (905mg, 4.39mmol, 5 equiv.) Was added to aqueous NaOH (30%, 4ml) and the mixture of Et 2 O (4ml) of at 0 ℃. After stirring at 0 ° C for 20 minutes, the color of the organic phase turned yellow, indicating the ability to prepare a solution of diazomethane in Et 2 O. To a suspension of compound 14-8 (416.5 mg, 878 μmol) and Pd(OAc) 2 (39.4 mg, 176 μmol, 0.2 eq.) in Et 2 O (4 ml) was added in a separate flask at -30 ° C. A solution of nitrogen methane in Et 2 O. The reaction mixture was stirred at -20 ° C, and the Et 2 O solution (5 x 5 equivalents) and Pd (OAc) 2 (0.2 x 2 equivalents) of the above-prepared diazomethane were added in several batches until the compound 14- 8 is completely exhausted. After stirring at -20 ° C for 3 h from the first addition of the diazomethane solution, the reaction mixture was quenched with H 2 O and AcOH. A saturated aqueous solution of NaHCO 3 was added and the resulting mixture was filtered through a pad of Celite (registered trademark). The filtrate was washed with AcOEt. The aqueous phase was extracted with AcOEt. Dried over Na 2 SO 4, and the organic phase was concentrated. The residue was purified by silica gel chromatography to afford compound 14-9 (259.2mg, 531.

1H-NMR(CDCl3)δ：0.75-1.20(m,4H),1.43(s,3H),1.47(s,9H),4.25(dd,J=28.5,10.7Hz,1H),5.27(d,J=47.6Hz,1H),7.05(m,1H),7.17(m,1H),7.29(m,1H),7.40-7.61(m,4H),7.76(m,2H)。 1 H-NMR (CDCl 3 ) δ: 0.75-1.20 (m, 4H), 1.43 (s, 3H), 1.47 (s, 9H), 4.25 (dd, J = 28.5, 10.7 Hz, 1H), 5. , J = 47.6 Hz, 1H), 7.05 (m, 1H), 7.17 (m, 1H), 7.29 (m, 1H), 7.40 - 7.61 (m, 4H), 7.76 (m, 2H).

步驟9 Step 9

在室溫下向化合物14-9(259.2mg，531μmol)於MeOH(5ml)中之溶液中添加K2CO3(367mg，2.65mmol)。在室溫下攪拌20分鐘之後，用H2O淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機相且濃縮。藉由矽膠層析純化殘餘物，獲得化合物14-10(117.4mg，305μmol，58%)。 K 2 CO 3 (367 mg, 2.65 mmol) was added to a solution of compound 14-9 (259.2 mg, 531. After stirring at room temperature for 20 minutes, the reaction was quenched with H 2 O mixture. The aqueous phase was extracted with AcOEt. Dried over Na 2 SO 4, and the organic phase was concentrated. The residue was purified by silica gel chromatography to afford compound 14-10 (117.4 mg, 305.

1H-NMR(CDCl3)δ：0.84-1.17(m,4H),1.52(s,9H),1.85(s,3H),4.35(dd,J=28.1,5.3Hz,1H),5.48(d,J=46.9Hz,1H),7.14(m,1H),7.24(m,1H),7.35-7.44(m,2H),10.00(brs,1H)。 1 H-NMR (CDCl 3 ) δ: 0.84-1.17 (m, 4H), 1.52 (s, 9H), 1.85 (s, 3H), 4.35 (dd, J = 28.1, 5.3 Hz, 1H), 5.48 (d) , J = 46.9 Hz, 1H), 7.14 (m, 1H), 7.24 (m, 1H), 7.35-7.44 (m, 2H), 10.00 (brs, 1H).

步驟10 Step 10

在室溫下將化合物14-10(117.4mg，305μmol)溶解於TFA(1ml) 中。在室溫下攪拌1h之後，將反應混合物冷卻至-20℃，接著添加H2SO4(250μl)。在0℃下攪拌5分鐘之後，將反應混合物冷卻至-20℃，隨後添加HNO3(41μl，916μmol)。在0℃下攪拌25分鐘之後，用K2CO3水溶液淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機相且濃縮。藉由矽膠層析純化殘餘物，獲得化合物14-11(82.8mg，251μmol，82%)。 Compound 14-10 (117.4 mg, 305 μmol) was dissolved in TFA (1 mL) at room temperature. After stirring at room temperature for 1 h, the reaction mixture was cooled to -20 ° C then H 2 SO 4 (250 μl). After stirring at 0 ° C for 5 minutes, the reaction mixture was cooled to -20 ° C, then HNO 3 (41 μl, 916 μmol) was added. After stirring for 25 minutes at 0 ℃, with K 2 CO 3 solution to quench the reaction mixture. The aqueous phase was extracted with AcOEt. Dried over Na 2 SO 4, and the organic phase was concentrated. The residue was purified by silica gel chromatography to afford compound 14-11 (82.8 mg, 251.

1H-NMR(CDCl3)δ：0.81(m,1H),0.91-1.07(m,2H),1.13(m,1H),1.66(s,3H),4.05(dd,J=29.1,9.9Hz,1H),4.35(brs,2H),5.33(d,J=47.6Hz,1H),7.23(dd,J=10.7,9.0Hz,1H),8.21(ddd,J=9.0,4.1,2.9Hz,1H),8.46(dd,J=6.7,2.9Hz,1H)。 1 H-NMR (CDCl 3 ) δ: 0.81 (m, 1H), 0.91-1.07 (m, 2H), 1.13 (m, 1H), 1.66 (s, 3H), 4.05 (dd, J = 29.1, 9.9 Hz , 1H), 4.35 (brs, 2H), 5.33 (d, J = 47.6 Hz, 1H), 7.23 (dd, J = 10.7, 9.0 Hz, 1H), 8.21 (ddd, J = 9.0, 4.1, 2.9 Hz, 1H), 8.46 (dd, J = 6.7, 2.9 Hz, 1H).

步驟11 Step 11

在室溫下向化合物14-11(82.8mg，251μmol)及Boc2O(175μl，754μmol)於CH2Cl2(1ml)中之溶液中添加DMAP(30.7mg，251μmol)。在室溫下攪拌30分鐘之後，濃縮反應混合物。藉由矽膠層析純化殘餘物，獲得化合物14-12(83.8mg，158μmol，63%)。 To a solution of the compound 14-11 (82.8 mg, 251 μmol) and Boc 2 O (175 μl, 754 μmol) in CH 2 Cl 2 (1 ml) was added DMAP (30.7 mg, 251 μmol). After stirring at room temperature for 30 minutes, the reaction mixture was concentrated. The residue was purified by silica gel chromatography to afford compound 14-12 (83.8 mg, 158.

1H-NMR(CDCl3)δ：0.80(m,1H),0.92-1.09(m,2H),1.16(m,1H),1.53(s,18H),1.74(s,3H),4.23(dd,J=28.2,8.2Hz,1H),5.39(d,J=47.1Hz,1H),7.28(m,1H),8.26(m,1H),8.56(dd,J=6.7,2.9Hz,1H)。 1 H-NMR (CDCl 3 ) δ: 0.80 (m, 1H), 0.92-1.09 (m, 2H), 1.16 (m, 1H), 1.53 (s, 18H), 1.74 (s, 3H), 4.23 (dd , J=28.2, 8.2 Hz, 1H), 5.39 (d, J=47.1 Hz, 1H), 7.28 (m, 1H), 8.26 (m, 1H), 8.56 (dd, J=6.7, 2.9 Hz, 1H) .

步驟12 Step 12

在室溫下向化合物14-12(83.8mg，158μmol)於THF(0.5ml)及MeOH(1ml)中之溶液中添加Pd/C(8.4mg)。在室溫下在H2氛圍下攪拌4.5h之後，經由矽藻土(註冊商標)墊過濾反應混合物，且用AcOEt洗滌殘餘物。濃縮濾液，且藉由矽膠層析純化殘餘物，獲得化合物14-13(65.4mg，131μmol，83%)。 To a solution of the compound 14-12 (83.8 mg, 158 [mu]mol) in THF (0.5 ml) and MeOH (1 ml) was added Pd/C (8.4 mg). After stirring at room temperature for 4.5 h under H 2 atmosphere, the reaction mixture was filtered through a pad of Celite (registered trademark), and the residue was washed with AcOEt. The filtrate was concentrated, and the residue was purifiedjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

1H-NMR(CDCl3)δ：0.75-1.20(m,4H),1.52(s,18H),1.70(m, 3H),3.57(brs,2H),4.31(dd,J=28.6,10.0Hz,1H),5.35(d,J=47.7Hz,1H),6.56(m,1H),6.83-6.90(m,2H)。 1 H-NMR (CDCl 3 ) δ: 0.75-1.20 (m, 4H), 1.52 (s, 18H), 1.70 (m, 3H), 3.57 (brs, 2H), 4.31 (dd, J = 28.6, 10.0 Hz , 1H), 5.35 (d, J = 47.7 Hz, 1H), 6.56 (m, 1H), 6.83-6.90 (m, 2H).

步驟13 Step 13

在室溫下向化合物14-13(41.0mg，82μmol)、5-(氟甲氧基)吡-2-甲酸(17.0mg，98μmol)及二異丙基乙胺(29μl，164μmol)於DMF(2ml)中之溶液中添加HATU(37.5mg，98μmol)。在室溫下攪拌1h之後，用NH4Cl飽和水溶液淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機相且濃縮。藉由矽膠層析純化殘餘物，獲得化合物14-14(49.4mg，76μmol，92%)。 To compound 14-13 (41.0 mg, 82 μmol), 5-(fluoromethoxy)pyrene at room temperature HATU (37.5 mg, 98 μmol) was added to a solution of 2-carboxylic acid (17.0 mg, 98 μmol) and diisopropylethylamine (29 μl, 164 μmol) in DMF (2 mL). After stirring at room temperature for 1h, with saturated aqueous NH 4 Cl the reaction mixture was quenched. The aqueous phase was extracted with AcOEt. Dried over Na 2 SO 4, and the organic phase was concentrated. The residue was purified by silica gel chromatography to afford compound 14-14 (49.4mg, 76.

1H-NMR(CDCl3)δ：0.75-1.22(m,4H),1.55(s,18H),1.76(m,3H),4.29(dd,J=29.1,9.9Hz,1H),5.37(d,J=47.4Hz,1H),6.15(ddd,J=51.1,13.6,2.0Hz,2H),7.15(dd,J=11.5,9.0Hz,1H),7.51(dd,J=6.8,2.8Hz,1H),8.19(d,J=1.3Hz,1H),8.37(ddd,J=9.0,4.3,2.8Hz,1H),9.08(d,J=1.3Hz,1H),9.64(s,1H)。 1 H-NMR (CDCl 3 ) δ: 0.75-1.22 (m, 4H), 1.55 (s, 18H), 1.76 (m, 3H), 4.29 (dd, J = 29.1, 9.9 Hz, 1H), 5.37 (d) , J=47.4 Hz, 1H), 6.15 (ddd, J=51.1, 13.6, 2.0 Hz, 2H), 7.15 (dd, J=11.5, 9.0 Hz, 1H), 7.51 (dd, J=6.8, 2.8 Hz, 1H), 8.19 (d, J = 1.3 Hz, 1H), 8.37 (ddd, J = 9.0, 4.3, 2.8 Hz, 1H), 9.08 (d, J = 1.3 Hz, 1H), 9.64 (s, 1H).

步驟14 Step 14

在室溫下將化合物14-14(49.4mg，76μmol)溶解於甲酸(1ml，26.1mmol)中。在室溫下攪拌16.5h之後，用K2CO3水溶液淬滅反應混合物。用AcOEt萃取水相。經Na2SO4乾燥有機相且濃縮。藉由自己烷凝固純化殘餘物，得到純I-94(25.9mg，57μmol，76%)。 Compound 14-14 (49.4 mg, 76 μmol) was dissolved in formic acid (1 mL, 26.1 mmol) at room temperature. After 16.5h stirring at room temperature with K 2 CO 3 solution the reaction mixture was quenched. The aqueous phase was extracted with AcOEt. Dried over Na 2 SO 4, and the organic phase was concentrated. The residue was purified by hexane to afford pure I-94 (25.9 mg, 57.

1H-NMR(CDCl3)δ：0.76-1.20(m,4H),1.67(s,3H),4.11(dd,J=29.2,11.8Hz,1H),5.35(d,J=47.9Hz,1H),6.15(m,2H),7.11(dd,J=11.3,8.9Hz,1H),7.50(dd,J=6.8,2.6Hz,1H),8.02(m,1H),8.29(s,1H),9.08(s,1H),9.52(s,1H)。 1 H-NMR (CDCl 3 ) δ: 0.76-1.20 (m, 4H), 1.67 (s, 3H), 4.11 (dd, J = 29.2, 11.8 Hz, 1H), 5.35 (d, J = 47.9 Hz, 1H) ), 6.15 (m, 2H), 7.11 (dd, J = 11.3, 8.9 Hz, 1H), 7.50 (dd, J = 6.8, 2.6 Hz, 1H), 8.02 (m, 1H), 8.29 (s, 1H) , 9.08 (s, 1H), 9.52 (s, 1H).

以與上文類似之方式製備以下化合物。在以下各表中，RT意謂LC/MS滯留時間(分鐘)。 The following compounds were prepared in a similar manner as above. In the following tables, RT means LC/MS residence time (minutes).

[表1-1] [Table 1-1]

[表1-3] [Table 1-3]

本發明化合物之測試實例為如下文所述。 Test examples of the compounds of the invention are described below.

(測試實例1-1：BACE1抑制活性之分析：96孔) (Test Example 1-1: Analysis of BACE1 inhibitory activity: 96 wells)

將48.5μL受質肽溶液(生物素-XSEVNLDAEFRHDSGC-Eu：X=ε-胺基正己酸，Eu=銪穴狀化合物)添加至96孔半區盤(黑色盤：Costar)之各孔中，且在添加0.5μl本發明化合物(DMSO溶液)及1μl重組人類BACE1(R&D Systems)之後，在30℃下培育反應混合物3.5小時。藉由 使穴狀化合物TBPCOOH mono SMP(CIS bio international)與生物素-XSEVNLDAEFRHDSGC(Peptide Institute,Inc.)反應合成受質肽。將受質肽及重組人類BACE1之最終濃度分別調節至9.7nmol/L及500nmol/L，且在乙酸鈉緩衝液(50mmol/L乙酸鈉，pH 5.0，0.008%Triton X-100)中進行反應。 48.5 μL of the peptide solution (Biotin-XSEVNLDAEFRHDSGC-Eu: X=ε-amino hexanoic acid, Eu=铕 cryptate) was added to each well of a 96-well half-disc (black plate: Costar), and After adding 0.5 μl of the compound of the present invention (DMSO solution) and 1 μl of recombinant human BACE1 (R&D Systems), the reaction mixture was incubated at 30 ° C for 3.5 hours. By The dentate compound TBPCOOH mono SMP (CIS bio international) was reacted with biotin-XSEVNLDAEFRHDSGC (Peptide Institute, Inc.) to synthesize a peptide. The final concentrations of the receptor peptide and recombinant human BACE1 were adjusted to 9.7 nmol/L and 500 nmol/L, respectively, and the reaction was carried out in a sodium acetate buffer (50 mmol/L sodium acetate, pH 5.0, 0.008% Triton X-100).

在用於反應之培育之後，將50μl溶解於磷酸鹽緩衝液(150mmol/L K2HPO4-KH2PO4，pH 7.0，0.008%TritonX-100，0.8mol/L KF)中之8.0μg/ml抗生蛋白鏈菌素-XL665(CIS bio international)添加至各孔中且在30℃下保持靜置45分鐘。隨後，使用ARVO-X4 2030多標記讀取器(Perkin Elmer life sciences)量測螢光強度(激發波長：320nm，量測波長：620nm及665nm)。利用各波長之計數比(10,000×計數665/計數620)測定酶活性且計算針對酶活性之50%抑制濃度(IC50)。 After the reaction for growing the 50μl was dissolved in phosphate buffer (150mmol / LK 2 HPO 4 -KH 2 PO 4, pH 7.0,0.008% TritonX-100,0.8mol / L KF) in the 8.0μg / ml Streptavidin-XL665 (CIS bio international) was added to each well and allowed to stand at 30 ° C for 45 minutes. Subsequently, the fluorescence intensity (excitation wavelength: 320 nm, measurement wavelength: 620 nm and 665 nm) was measured using an ARVO-X4 2030 multi-label reader (Perkin Elmer life sciences). Enzyme activity was measured and calculated inhibitory concentration (IC 50) for 50% of the activity ratio of (10,000 × Count 665 / Count 620) using the counts for each wavelength.

(測試實例1-2：BACEI抑制活性之分析：384孔) (Test Example 1-2: Analysis of BACEI inhibitory activity: 384 wells)

將5μL受質肽溶液(生物素-XSEVNLDAEFRHDSGC-Eu：X=ε-胺基正己酸，Eu=銪穴狀化合物)添加至384孔盤(黑色盤：Corning)之各孔中，且在添加0.1μl本發明化合物(DMSO溶液)及5μl重組人類BACE1(R&D Systems)之後，在25℃下培育反應混合物2小時。藉由使穴狀化合物TBPCOOH mono SMP(CIS bio international)與生物素-XSEVNLDAEFRHDSGC(Peptide Institute,Inc.)反應合成受質肽。將受質肽及重組人類BACE1之最終濃度分別調節至9.7nmol/L及500nmol/L，且在乙酸鈉緩衝液(50mmol/L乙酸鈉，pH 5.0，0.008%Triton X-100)中進行反應。 5 μL of the peptide solution (Biotin-XSEVNLDAEFRHDSGC-Eu: X=ε-aminohexanoic acid, Eu=铕 cryptate) was added to each well of a 384-well plate (black plate: Corning), and 0.1 was added. After μl of the compound of the invention (DMSO solution) and 5 μl of recombinant human BACE1 (R&D Systems), the reaction mixture was incubated at 25 ° C for 2 hours. The peptide was synthesized by reacting the cryptic compound TBPCOOH mono SMP (CIS bio international) with biotin-XSEVNLDAEFRHDSGC (Peptide Institute, Inc.). The final concentrations of the receptor peptide and recombinant human BACE1 were adjusted to 9.7 nmol/L and 500 nmol/L, respectively, and the reaction was carried out in a sodium acetate buffer (50 mmol/L sodium acetate, pH 5.0, 0.008% Triton X-100).

在用於反應之培育之後，將10μl溶解於磷酸鹽緩衝液(150mmol/L K2HPO4-KH2PO4，pH 7.0，0.008%TritonX-100，0.8mol/L KF)中之8.0μg/ml抗生蛋白鏈菌素-XL665(CIS bio international)添加至各孔中且在25℃下保持靜置30分鐘。隨後，使用RUBYstar(BMG LABTECH)量測螢光強度(激發波長：320nm，量測波長：620nm及665nm)。利用各波長之計數比(10,000×計數665/計數620)測定酶活性且計算針對酶活性之50%抑制濃度(IC50)。 After the reaction for growing the 10μl was dissolved in phosphate buffer (150mmol / LK 2 HPO 4 -KH 2 PO 4, pH 7.0,0.008% TritonX-100,0.8mol / L KF) in the 8.0μg / ml Streptavidin-XL665 (CIS bio international) was added to each well and allowed to stand at 25 ° C for 30 minutes. Subsequently, the fluorescence intensity (excitation wavelength: 320 nm, measurement wavelength: 620 nm and 665 nm) was measured using RUBYstar (BMG LABTECH). Enzyme activity was measured and calculated inhibitory concentration (IC 50) for 50% of the activity ratio of (10,000 × Count 665 / Count 620) using the counts for each wavelength.

(測試實例1-3：BACE2抑制活性之分析) (Test Example 1-3: Analysis of BACE2 inhibitory activity)

將89μL受質肽溶液(SEVNLDAEFRHDSGYEK-生物素)添加至96孔盤(黑色盤：Costar)之各孔中，且在添加1μl本發明化合物(DMSO溶液)及10μl人類BACE2(表現人類BACE2胞外域之經純化FreeStyle TM293-F細胞條件培養基)之後，在37℃下培育反應混合物1小時。將受質肽及人類BACE2之最終濃度分別調節至1000nmol/L及20ng/mL，且在乙酸鈉緩衝液(50mmol/L乙酸鈉，pH 4.5，0.25mg/mL牛血清白蛋白)中進行反應。 89 μL of the peptide solution (SEVNLDAEFRHDSGYEK-Biotin) was added to each well of a 96-well plate (black plate: Costar), and 1 μl of the compound of the present invention (DMSO solution) and 10 μl of human BACE2 (expressing the human BACE2 extracellular domain) were added. After purification of FreeStyleTM 293-F cell conditioned medium), the reaction mixture was incubated at 37 °C for 1 hour. The final concentrations of the receptor peptide and human BACE2 were adjusted to 1000 nmol/L and 20 ng/mL, respectively, and the reaction was carried out in a sodium acetate buffer (50 mmol/L sodium acetate, pH 4.5, 0.25 mg/mL bovine serum albumin).

在用於反應之培育之後，將30μl 1M Tris-HCL(pH 7.6)添加至反應混合物中。將反應混合物添加至塗有82E1(抗澱粉狀蛋白β抗體；Immuno-Biological Loboratories)之各孔中且在4℃下培育隔夜。在培育及五次洗滌之後，將中性鏈親和素-辣根過氧化酶結合物(Thermo Fisher)添加至各孔中且在室溫下培育1小時。在五次洗滌之後，將Supersignal pico溶液A及B(Thermo Fisher)之45μL混合物添加至各孔中。藉由ARVO MX 1420多標記讀取器(Perkin Elmer life sciences)量測各孔中之化學發光計數。利用各波長之計數比(10,000×計數665/計數620)測定酶活性且計算針對酶活性之50%抑制濃度(IC50)。 After the incubation for the reaction, 30 μl of 1 M Tris-HCL (pH 7.6) was added to the reaction mixture. The reaction mixture was added to each well coated with 82E1 (anti-amyloid β antibody; Immuno-Biological Loboratories) and incubated overnight at 4 °C. After incubation and five washes, a neutral streptavidin-horseradish peroxidase conjugate (Thermo Fisher) was added to each well and incubated for 1 hour at room temperature. After five washes, 45 μL of a mixture of Supersignal pico solutions A and B (Thermo Fisher) was added to each well. Chemiluminescence counts in each well were measured by an ARVO MX 1420 multi-label reader (Perkin Elmer life sciences). Determination of enzyme activity and inhibition calculated concentration (IC 50) for 50% of the activity ratio of (10,000 × Count 665 / Count 620) using the counts for each wavelength.

(測試實例2-1：量測細胞中之β-澱粉狀蛋白(Aβ)產生抑制效應：96孔) (Test Example 2-1: Measurement of β-amyloid (Aβ) production inhibitory effect in cells: 96 wells)

在以8×105個細胞/毫升製備其中人類野生型β-APP受到過度表現之神經母細胞瘤SH-SY5Y細胞(SH/APPwt)，且將其150μL部分接種至96孔培養盤(Falcon)之各孔中。在37℃下在5%氣態二氧化碳恆溫箱中培養細胞2小時。隨後，將已藉由添加及懸浮本發明化合物(DMSO(二甲亞碸)溶液)以便達成2μl/50μl培養基而預先製備之溶液添加至細胞液中。亦即最終DMSO濃度為1%，且細胞培養物之量為200μl。自添加測試化合物開始培育24小時之後，自各溶離份收集100μl培養上清液。量測各溶離份中之Aβ之量。 Neuroblastoma SH-SY5Y cells (SH/APPwt) in which human wild-type β-APP was overexpressed were prepared at 8×10 5 cells/ml, and 150 μL of the cells were partially inoculated into a 96-well culture plate (Falcon). In each hole. The cells were incubated for 2 hours at 37 ° C in a 5% gaseous carbon dioxide incubator. Subsequently, a solution which has been previously prepared by adding and suspending the compound of the present invention (DMSO (dimethyl sulfonium) solution) to obtain 2 μl / 50 μl of the medium is added to the cell liquid. That is, the final DMSO concentration was 1%, and the amount of the cell culture was 200 μl. After incubation for 24 hours from the addition of the test compound, 100 μl of the culture supernatant was collected from each fraction. The amount of Aβ in each fraction was measured.

如下量測Aβ量。將10μl均相時差式螢光(HTRF)量測試劑(澱粉狀蛋白β 1-40肽；CIS bio international)及10μl培養上清液放入384孔半區微量盤(黑色微量盤，Costar)中且彼此混合，接著在遮蔽光時在4℃下保持靜置隔夜。隨後，藉由微盤讀取器(Artemis K-101；FURUNO ELECTRIC)量測螢光強度(激發波長：337nm，量測波長：620nm及665nm)。利用各量測波長下之計數比(10000×計數665/計數620)測定Aβ量，且利用至少六種不同劑量計算將Aβ產生抑制50%所需的量(IC50)。 The amount of Aβ was measured as follows. 10 μl of homogenous time difference fluorescence (HTRF) amount tester (amyloid β 1-40 peptide; CIS bio international) and 10 μl of culture supernatant were placed in a 384-well half-region microplate (black microplate, Costar) They were mixed with each other and then left to stand overnight at 4 ° C while shielding the light. Subsequently, the fluorescence intensity (excitation wavelength: 337 nm, measurement wavelength: 620 nm and 665 nm) was measured by a microdisk reader (Artemis K-101; FURUNO ELECTRIC). The Aβ amount was determined using the count ratio at each measurement wavelength (10000 × count 665 / count 620), and the amount (IC 50 ) required to inhibit Aβ production by 50% was calculated using at least six different doses.

(測試實例2-2：量測細胞中之β-澱粉狀蛋白(Aβ)產生抑制效應：384孔) (Test Example 2-2: Measurement of β-amyloid (Aβ) production inhibition effect in cells: 384 wells)

以4×105個細胞/毫升製備其中人類野生型β-APP受到過度表現之神經母細胞瘤SH-SY5Y細胞(SH/APPwt)，且將其50μl部分接種至添加有0.5μl本發明測試化合物(DMSO溶液)之384孔培養盤(Corning)之各孔中。最終DMSO濃度為1%，且細胞培養物之量為50μl。自細胞接種開始培育24小時之後，自各溶離份收集5μl培養上清液。量測各溶離份中之Aβ之量。 Neuroblastoma SH-SY5Y cells (SH/APPwt) in which human wild-type β-APP was overexpressed were prepared at 4×10 5 cells/ml, and 50 μl thereof was partially inoculated to 0.5 μl of the test compound of the present invention. (DMSO solution) in each well of a 384-well culture plate (Corning). The final DMSO concentration was 1% and the amount of cell culture was 50 μl. After 24 hours from the start of cell seeding, 5 μl of the culture supernatant was collected from each fraction. The amount of Aβ in each fraction was measured.

如下量測Aβ量。將5μl均相時差式螢光(HTRF)量測試劑(澱粉狀蛋白β 1-40肽；CIS bio international)及5μl培養上清液放入384孔盤 (黑色盤：Corning)中且彼此混合，接著在遮蔽光時在4℃下保持靜置隔夜。隨後，藉由EnVision(Perkin Elmer life sciences)量測螢光強度(620nm及665nm)。利用各量測波長下之計數比(計數665/計數620)測定Aβ量，且利用至少六種不同劑量計算將Aβ產生抑制50%所需的量(IC50)。 The amount of Aβ was measured as follows. 5 μl of a homogeneous time difference fluorescence (HTRF) amount test agent (amyloid β 1-40 peptide; CIS bio international) and 5 μl of the culture supernatant were placed in a 384-well plate (black plate: Corning) and mixed with each other. It was then left to stand overnight at 4 ° C while shielding the light. Subsequently, the fluorescence intensity (620 nm and 665 nm) was measured by EnVision (Perkin Elmer life sciences). The amount of Aβ was determined using the count ratio at each measurement wavelength (count 665 / count 620), and the amount (IC 50 ) required to inhibit Aβ production by 50% was calculated using at least six different doses.

(測試實例3-1：對大鼠中之腦β澱粉狀蛋白之降低效應) (Test Example 3-1: Reduction effect on brain β-amyloid in rats)

將本發明化合物懸浮於0.5%甲基纖維素中，將最終濃度調節至2mg/mL，且以10mg/kg向雄性Crl：SD大鼠(7至9週齡)經口投與此懸浮物。在媒劑對照組中，僅投與0.5%甲基纖維素，且以每組3至8隻動物進行投與測試。在投與之後3小時分離腦，分離腦半球，量測其重量，在液氮中快速冷凍該半球，且在-80℃下儲存直至萃取日期。將冷凍腦半球轉移至藉由Teflon(註冊商標)在冰冷卻下製造之均質機，添加重量之4倍體積之萃取緩衝液(含有1%CHAPS({3-[(3-氯醯胺丙基)二甲基銨基]-1-丙烷磺酸酯})、20mmol/L Tris-HCl(pH 8.0)、150mmol/L NaCl、Complete(Roche)蛋白酶抑制劑)，重複上下運動，且此物質持續2分鐘經均質化以溶解。將懸浮液轉移至離心導管，使其在冰上靜置3小時或3小時以上，且此後在100,000×g、4℃下離心20分鐘。在離心之後，將上清液轉移至ELISA盤(產品號294-62501,Wako Junyaku Kogyo)以量測β澱粉狀蛋白40。根據隨附說明書進行ELISA量測。以相比於各測試之媒劑對照組之腦β澱粉狀蛋白40含量之比率計算降低效應。 The compound of the present invention was suspended in 0.5% methylcellulose, the final concentration was adjusted to 2 mg/mL, and the suspension was orally administered to male Crl: SD rats (7 to 9 weeks old) at 10 mg/kg. In the vehicle control group, only 0.5% methylcellulose was administered, and administration tests were performed in groups of 3 to 8 animals. The brain was isolated 3 hours after administration, the brain hemisphere was separated, the weight was measured, the hemisphere was rapidly frozen in liquid nitrogen, and stored at -80 ° C until the extraction date. The frozen brain hemisphere was transferred to a homogenizer manufactured by Teflon (registered trademark) under ice cooling, and 4 times the volume of the extraction buffer (containing 1% CHAPS ({3-[(3-chloroproguanylpropyl)) was added. ) dimethylammonio]-1-propane sulfonate}), 20 mmol/L Tris-HCl (pH 8.0), 150 mmol/L NaCl, Complete (Roche) protease inhibitor, repeated up and down movement, and the substance continues It was homogenized for 2 minutes to dissolve. The suspension was transferred to a centrifuge tube and allowed to stand on ice for 3 hours or more, and thereafter centrifuged at 100,000 x g, 4 ° C for 20 minutes. After centrifugation, the supernatant was transferred to an ELISA plate (product number 294-62501, Wako Junyaku Kogyo) to measure beta amyloid 40. ELISA measurements were performed according to the accompanying instructions. The reduction effect was calculated as the ratio of brain beta amyloid 40 content to the vehicle control group of each test.

(測試實例3-2：對小鼠中之腦β澱粉狀蛋白之降低效應) (Test Example 3-2: Reduction effect on brain beta amyloid in mice)

將本發明化合物溶解於20%羥基-β-環糊精中，將最終濃度調節至2mg/mL，且以1至10mg/kg向雄性Crl：CD1(ICR)小鼠(6至8週齡)經口投與此混合物。在媒劑對照組中，僅投與20%羥基-β-環糊精，且以3至6隻動物/組進行投與測試。在投與之後1至6小時分離腦，分離腦半球，量測其重量，在液氮中快速冷凍該半球，且在-80℃下儲存直至萃取日期。 The compound of the present invention was dissolved in 20% hydroxy-β-cyclodextrin, the final concentration was adjusted to 2 mg/mL, and the male Crl:CD1 (ICR) mouse (6 to 8 weeks old) was administered at 1 to 10 mg/kg. This mixture is orally administered. In the vehicle control group, only 20% hydroxy-β-cyclodextrin was administered, and administration tests were performed in 3 to 6 animals/group. The brain was isolated 1 to 6 hours after administration, the brain hemisphere was separated, the weight was measured, the hemisphere was rapidly frozen in liquid nitrogen, and stored at -80 ° C until the extraction date.

將冷凍腦半球轉移至重量之8倍體積之萃取緩衝液(含有0.4%DEA(二乙胺)、50mmol/L NaCl、Complete蛋白酶抑制劑(Roche))中含有陶瓷珠粒之均勻化導管且在冰上培育20分鐘。此後，使用具有裂解受質D 1.4mm陶瓷珠粒之MP BIO FastPrep(註冊商標)-24進行均質化(20秒，6m/s)。隨後，導管旋轉減慢1分鐘，將上清液轉移至離心導管，且在221,000×g、4℃下離心50分鐘。在離心之後，將上清液轉移至Nunc Maxisorp(註冊商標)盤(Thermo Fisher Scientific)，該盤塗佈有相對於β澱粉狀蛋白之N末端之抗體以量測總β澱粉狀蛋白，且在4℃下培育盤隔夜。用TBS-T(Tris緩衝生理鹽水，含有0.05%Triton X-100)洗滌盤，且在盤中添加溶解於含有0.1%酪蛋白之PBS(pH 7.4)中之HRP共軛4G8且在4℃下培育1小時。在用TBS-T對其進行洗滌之後，將SuperSignal ELISA Pico化學發光受質(Thermo Scientific)添加至盤中。隨後，儘可能快地藉由ARVO(註冊商標)MX 1420多標記計數器(Perkin Elmer)量測化學發光計數。以相比於各測試之媒劑對照組之腦總β澱粉狀蛋白含量之比率計算降低效應。 The frozen brain hemisphere was transferred to a weight-enhanced extraction buffer (containing 0.4% DEA (diethylamine), 50 mmol/L NaCl, Complete protease inhibitor (Roche)) containing a ceramic bead homogenized catheter and Incubate on ice for 20 minutes. Thereafter, homogenization (20 sec, 6 m/s) was carried out using MP BIO FastPrep (registered trademark)-24 having a cleavage substrate D 1.4 mm ceramic beads. Subsequently, the catheter was rotated for 1 minute, the supernatant was transferred to a centrifuge catheter, and centrifuged at 221,000 x g, 4 ° C for 50 minutes. After centrifugation, the supernatant was transferred to a Nunc Maxisorp (registered trademark) disk (Thermo Fisher Scientific) coated with an antibody against the N-terminus of amyloid beta to measure total beta amyloid, and The plates were incubated overnight at 4 °C. The plate was washed with TBS-T (Tris buffered saline containing 0.05% Triton X-100), and HRP conjugated 4G8 dissolved in 0.1% casein in PBS (pH 7.4) was added to the plate at 4 ° C. Incubate for 1 hour. After washing with TBS-T, SuperSignal ELISA Pico Chemiluminescence (Thermo Scientific) was added to the dish. Subsequently, the chemiluminescence count was measured as fast as possible by the ARVO (registered trademark) MX 1420 multi-label counter (Perkin Elmer). The reduction effect was calculated as the ratio of the total beta amyloid content of the brain to the vehicle control group of each test.

(測試實例4-1：CYP3A4螢光MBI測試) (Test Example 4-1: CYP3A4 Fluorescent MBI Test)

CYP3A4螢光MBI測試為研究化合物之CYP3A4抑制藉由代謝反應之增強之測試。7-苯甲氧基三氟甲基香豆素(7-BFC)藉由CYP3A4酶(表現於大腸桿菌中之酶)脫苯甲基且產生螢光代謝物形式之7-羥基三氟甲基香豆素(7-HFC)。使用7-HFC產生反應作為指數進行測試。 The CYP3A4 fluorescent MBI test is a test for the enhancement of CYP3A4 inhibition by a metabolic reaction of a compound. 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by the CYP3A4 enzyme (an enzyme expressed in E. coli) and produces a 7-hydroxytrifluoromethyl form in the form of a fluorescent metabolite Coumarin (7-HFC). The reaction was carried out using a 7-HFC reaction as an index.

反應條件為如下：受質，5.6μmol/L 7-BFC；預反應時間，0或30分鐘；受質反應時間，15分鐘；反應溫度，25℃(室溫)；CYP3A4含量(表現於大腸桿菌中)，在預反應時間處62.5pmol/mL，在反應時間處6.25pmol/mL(以10倍稀釋度)；本發明化合物之濃度，0.625、1.25、2.5、5、10、20μmol/L(六個點)。 The reaction conditions were as follows: substrate, 5.6 μmol/L 7-BFC; pre-reaction time, 0 or 30 minutes; substrate reaction time, 15 minutes; reaction temperature, 25 ° C (room temperature); CYP3A4 content (expressed in Escherichia coli Medium), 62.5 pmol/mL at pre-reaction time, 6.25 pmol/mL at reaction time (10-fold dilution); concentration of the compound of the invention, 0.625, 1.25, 2.5, 5, 10, 20 μmol/L (six a point).

將K-Pi緩衝液(pH 7.4)及本發明化合物溶液(作為預反應溶液)中之酶以預反應之組成添加至96孔盤。將一部分預反應溶液轉移至另一96孔盤，且藉由K-Pi緩衝液中之受質經1/10稀釋。添加作為輔因子之NADPH以起始反應，作為一個指數(在不預培育的情況下)。在預定反應時間之後，添加乙腈/0.5mol/L Tris(參羥基胺基甲烷)=4/1(v/v)溶液以停止反應。另一方面，亦將NADPH添加至殘留預反應溶液以起始預培育(在預培育之情況下)。在預定時間之預培育之後，將一部分轉移至另一96孔盤，且藉由K-Pi緩衝液中之受質經1/10稀釋以起始反應，作為一個指數。在預定反應時間之後，添加乙腈/0.5mol/L Tris(參羥基胺基甲烷)=4/1(v/v)溶液以停止反應。藉由螢光盤讀取器(Ex=420nm，Em=535nm)量測各指數反應盤中之代謝物形式之7-HFC之螢光值。 The enzyme in the K-Pi buffer (pH 7.4) and the compound solution of the present invention (as a pre-reaction solution) was added to a 96-well plate in a pre-reaction composition. A portion of the pre-reaction solution was transferred to another 96-well plate and diluted 1/10 by the substrate in the K-Pi buffer. NADPH was added as a cofactor to initiate the reaction as an index (without pre-incubation). After the predetermined reaction time, an acetonitrile / 0.5 mol / L Tris (hydroxyl aminomethane) = 4 / 1 (v / v) solution was added to stop the reaction. On the other hand, NADPH is also added to the residual pre-reaction solution to initiate pre-incubation (in the case of pre-incubation). After pre-incubation for a predetermined time, a portion was transferred to another 96-well plate, and the reaction was initiated by 1/10 dilution of the substrate in the K-Pi buffer as an index. After the predetermined reaction time, an acetonitrile / 0.5 mol / L Tris (hydroxyl aminomethane) = 4 / 1 (v / v) solution was added to stop the reaction. The fluorescence value of the 7-HFC in the form of a metabolite in each index reaction disk was measured by a fluorescent disc reader (Ex = 420 nm, Em = 535 nm).

將DMSO而非本發明化合物溶液添加至反應系統之樣品係用作對照物(100%)，因為DMSO用作溶解本發明化合物之溶劑。在以溶液形式添加之本發明化合物之各濃度下計算殘留活性(%)，且藉由使用濃度及抑制率之邏輯模型之反推計算IC50值。當預培育情況下之IC50值減去無預培育之情況下之IC50值的差值為5μM或5μM以上時，此定義為陽性(+)。當差值為3μM或3μM以下時，此定義為陰性(-)。 A sample which added DMSO instead of the compound solution of the present invention to the reaction system was used as a control (100%) because DMSO was used as a solvent for dissolving the compound of the present invention. The residual activity (%) was calculated at each concentration of the compound of the present invention added as a solution, and the IC 50 value was calculated by inverse calculation using a logical model of concentration and inhibition rate. When pre-incubated under the circumstances IC 50 IC 50 value is subtracted the value of the pre-incubated without 5μM of the difference is above or 5μM, defined herein as positive (+). When the difference is 3 μM or less, this is defined as negative (-).

以下化合物定義為陰性的。 The following compounds are defined as negative.

I-2、3、4、5、6、7、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、 33、34、36、40、41、42、43、44、45、71及86。 I-2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 36, 40, 41, 42, 43, 44, 45, 71 and 86.

(測試實例4-2：CYP3A4(MDZ)MBI測試) (Test Example 4-2: CYP3A4 (MDZ) MBI Test)

CYP3A4(MDZ)MBI測試為藉由增強代謝反應研究對化合物之CYP3A4抑制之機理性抑制(MBI)能力之測試。使用藉由彙集人肝微粒體之咪達唑侖(MDZ)之1-羥基化反應作為指數評估CYP3A4抑制。 The CYP3A4 (MDZ) MBI test is a test for the ability to inhibit the mechanism of CYP3A4 inhibition (MBI) of a compound by enhancing metabolic reactions. CYP3A4 inhibition was assessed using the 1-hydroxylation reaction of midazolam (MDZ) pooled with human liver microsomes as an index.

反應條件為如下：受質，10μmol/L MDZ；預反應時間，0或30分鐘；受質反應時間，2分鐘；反應溫度，37℃；彙集人肝微粒體之蛋白含量，在預反應時間處0.5mg/mL，在反應時間處0.05pmg/mL(以10倍稀釋度)；本發明化合物之濃度，1、5、10、20μmol/L(四個點)。 The reaction conditions are as follows: substrate, 10 μmol/L MDZ; pre-reaction time, 0 or 30 minutes; substrate reaction time, 2 minutes; reaction temperature, 37 ° C; protein content of human liver microsomes, at pre-reaction time 0.5 mg/mL, 0.05 pmg/mL (10-fold dilution) at the reaction time; concentration of the compound of the invention, 1, 5, 10, 20 μmol/L (four points).

將K-Pi緩衝液(pH 7.4)及本發明化合物溶液(作為預反應溶液)中之彙集人肝微粒體以預反應之組成添加至96孔盤。將一部分預反應溶液轉移至另一96孔盤，且藉由K-Pi緩衝液中之受質經1/10稀釋。添加作為輔因子之NADPH以起始反應，作為一個指數(在不預培育的情況下)。在預定反應時間之後，添加甲醇/乙腈=1/1(v/v)溶液以停止反應。另一方面，亦將NADPH添加至殘留預反應溶液以起始預培育(在預培育之情況下)。在預定時間之預培育之後，將一部分轉移至另一96孔盤，且藉由K-Pi緩衝液中之受質經1/10稀釋以起始反應，作為一個指數。在預定反應時間之後，添加甲醇/乙腈=1/1(v/v)溶液以停止反應。在3000轉/分鐘下離心15分鐘之後，藉由LC/MS/MS定量上清液中之1-羥基咪達唑侖。 The pooled human liver microsomes in K-Pi buffer (pH 7.4) and the compound solution of the present invention (as a pre-reaction solution) were added to a 96-well plate in a pre-reaction composition. A portion of the pre-reaction solution was transferred to another 96-well plate and diluted 1/10 by the substrate in the K-Pi buffer. NADPH was added as a cofactor to initiate the reaction as an index (without pre-incubation). After the predetermined reaction time, a methanol/acetonitrile = 1/1 (v/v) solution was added to stop the reaction. On the other hand, NADPH is also added to the residual pre-reaction solution to initiate pre-incubation (in the case of pre-incubation). After pre-incubation for a predetermined time, a portion was transferred to another 96-well plate, and the reaction was initiated by 1/10 dilution of the substrate in the K-Pi buffer as an index. After the predetermined reaction time, a methanol/acetonitrile = 1/1 (v/v) solution was added to stop the reaction. After centrifugation at 3000 rpm for 15 minutes, the 1-hydroxy midazolam in the supernatant was quantified by LC/MS/MS.

將DMSO而非本發明化合物溶液添加至反應系統之樣品係用作對照物(100%)，因為DMSO用作溶解本發明化合物之溶劑。在以溶液形式添加之本發明化合物之各濃度下計算殘留活性(%)，且藉由使用濃度及抑制率之邏輯模型之反推計算IC50值。以「0分鐘下之預培育之IC/30分鐘下之預培育之IC」計算移動IC值。當移動IC為1.5或1.5以上 時，此定義為陽性的。當移動IC為1.0或1.0以下時，此定義為陰性的。 A sample which added DMSO instead of the compound solution of the present invention to the reaction system was used as a control (100%) because DMSO was used as a solvent for dissolving the compound of the present invention. The residual activity (%) was calculated at each concentration of the compound of the present invention added as a solution, and the IC 50 value was calculated by inverse calculation using a logical model of concentration and inhibition rate. The mobile IC value was calculated with "IC pre-incubated at 0 minutes/pre-incubated IC at 30 minutes". This is defined as positive when the mobile IC is 1.5 or more. This is defined as negative when the mobile IC is 1.0 or less.

以下化合物定義為陰性的。 The following compounds are defined as negative.

I-50、52、54、56、64、65、75、77、81、82、88、89、90、91、94、108及109。 I-50, 52, 54, 56, 64, 65, 75, 77, 81, 82, 88, 89, 90, 91, 94, 108 and 109.

(測試實例5：CYP抑制測試) (Test Example 5: CYP inhibition test)

CYP抑制測試為分析本發明化合物對於人肝微粒體中之CYP酶之典型受質代謝反應之抑制效應的測試。如下使用五種人類主要CYP酶(CYP1A2、2C9、2C19、2D6及3A4)之標記物反應；O-去乙基化7-乙氧基試鹵靈(CYP1A2)、甲基-羥基化甲苯磺丁脲(CYP2C9)、4'-羥基化美芬妥英(mephenytoin)(CYP2C19)、O-去甲基化右甲嗎喃(CYP2D6)及羥基化特非那定(terfenadine)(CYP3A4)。將市售彙集人肝微粒體用作酶資源。 The CYP inhibition assay is a test to analyze the inhibitory effect of the compounds of the invention on the typical metabolic response of CYP enzymes in human liver microsomes. Labeling reactions using five human major CYP enzymes (CYP1A2, 2C9, 2C19, 2D6, and 3A4); O-deethylated 7-ethoxy resorufin (CYP1A2), methyl-hydroxylated toluene Urea (CYP2C9), 4'-hydroxylated mephenytoin (CYP2C19), O-demethylated dextromethorphan (CYP2D6) and hydroxylated terfenadine (CYP3A4). Commercially available human liver microsomes were used as enzyme resources.

反應條件如下：受質，0.5μmol/L乙氧基試鹵靈(CYP1A2)，100μmol/L甲苯磺丁脲(CYP2C9)，50μmol/L S-美芬妥英(CYP2C19)，5μmol/L右甲嗎喃(CYP2D6)，1μmol/L特非那定(CYP3A4)；反應時間，15分鐘；反應溫度，37℃；酶，彙集人肝微粒體0.2mg蛋白/毫升；本發明化合物之濃度，1、5、10、20μmol/L(四個點)。 The reaction conditions were as follows: substrate, 0.5 μmol/L ethoxylated resorufin (CYP1A2), 100 μmol/L tolbutamide (CYP2C9), 50 μmol/L S-mefentoin (CYP2C19), 5 μmol/L 右甲吗 ( (CYP2D6), 1 μmol/L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C; enzyme, pooling human liver microsomes 0.2 mg protein / ml; concentration of the compound of the invention, 1, 5, 10, 20 μmol / L (four points).

將50mmol/L Hepes緩衝液中之五種類型之受質、人肝微粒體及本發明之化合物溶液以如上文所述之組成添加至96孔盤中作為反應溶液。將作為輔因子之NADPH添加至此96孔盤中以起始代謝反應。在37℃下培育15分鐘之後，添加甲醇/乙腈=1/1(v/v)溶液以停止反應。 在3000轉/分鐘下離心15分鐘之後，藉由螢光盤讀取器定量上清液中之試鹵靈(CYP1A2代謝物)，且藉由LC/MS/MS定量上清液中之羥基甲苯磺丁脲(CYP2C9代謝物)、4'-羥基美芬妥英(CYP2C19代謝物)、右羥嗎喃(CYP2D6代謝物)及特非那定醇代謝物(CYP3A4代謝物)。 Five types of substrates, human liver microsomes, and a compound solution of the present invention in 50 mmol/L Hepes buffer were added to a 96-well plate as a reaction solution in a composition as described above. NADPH as a cofactor was added to this 96-well plate to initiate a metabolic reaction. After incubation at 37 ° C for 15 minutes, a methanol / acetonitrile = 1 / 1 (v / v) solution was added to stop the reaction. After centrifugation at 3000 rpm for 15 minutes, the resorufin (CYP1A2 metabolite) in the supernatant was quantified by a fluorescent disc reader, and the hydroxytoluene in the supernatant was quantified by LC/MS/MS. Butyl urea (CYP2C9 metabolite), 4'-hydroxymefentoin (CYP2C19 metabolite), dextromethorphan (CYP2D6 metabolite) and terfenadine alcohol metabolite (CYP3A4 metabolite).

將DMSO而非本發明化合物溶液添加至反應系統之樣品係用作對照物(100%)，因為DMSO用作溶解本發明化合物之溶劑。在本發明化合物之各濃度下計算殘留活性(%)，且藉由使用濃度及抑制率之邏輯模型之反推計算IC50值。 A sample which added DMSO instead of the compound solution of the present invention to the reaction system was used as a control (100%) because DMSO was used as a solvent for dissolving the compound of the present invention. The residual activity (%) was calculated at each concentration of the compound of the present invention, and the IC 50 value was calculated by inverse calculation using a logical model of concentration and inhibition rate.

CYP1A2>20μM：化合物I-1、2、3、4、5、6、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、30、31、32、33、34、35、36、40、41、42、43、44、45、46、47、48、49、50、51、52、53、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、94、108、109及116 CYP1A2>20 μM: Compounds I-1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 , 24, 25, 26, 27, 28, 30, 31, 32, 33, 34, 35, 36, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 , 53, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 94, 108, 109 and 116

CYP1A2>10μM：化合物I-29 CYP1A2>10μM: Compound I-29

CYP2C9>20μM：化合物I-1、10、12、13、14、15、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、40、41、42、43、44、45、55、56、57、58、59、60、61、71、78、86、87、88、89及90 CYP2C9>20 μM: Compounds I-1, 10, 12, 13, 14, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 , 33, 34, 35, 36, 40, 41, 42, 43, 44, 45, 55, 56, 57, 58, 59, 60, 61, 71, 78, 86, 87, 88, 89 and 90

CYP2C9>10μM：化合物I-2、3、4、5、11、16、49、62、63、75、77、79、80、81及94 CYP2C9>10 μM: Compounds I-2, 3, 4, 5, 11, 16, 49, 62, 63, 75, 77, 79, 80, 81 and 94

CYP2C19>20μM：化合物I-1、2、3、4、5、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、40、41、42、43、44、45、46、47、48、49、50、51、52、53、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、75、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、94、108、109及116 CYP2C19>20 μM: Compounds I-1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 , 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 , 53, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 75, 77, 78, 79, 80, 81, 82 , 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 94, 108, 109 and 116

CYP2C19>10μM：化合物I-6、76 CYP2C19>10μM: Compound I-6, 76

CYP2D6>20μM：化合物I-1、4、10、13、15、18、20、23、25、26、27、28、29、31、34、35、36、40、43、45、49、52、53、64、85、87、88、89、90及116 CYP2D6>20 μM: Compounds I-1, 4, 10, 13, 15, 18, 20, 23, 25, 26, 27, 28, 29, 31, 34, 35, 36, 40, 43, 45, 49, 52 , 53, 64, 85, 87, 88, 89, 90 and 116

CYP2D6>10μM：化合物I-11、12、22、24、32、44、46、48、70、78及108 CYP2D6>10 μM: Compounds I-11, 12, 22, 24, 32, 44, 46, 48, 70, 78 and 108

CYP3A4>20μM：化合物I-1、2、3、4、5、6、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、40、41、42、43、44、45、47、48、49、50、52、53、64、65、71、86、87、88、89、90、91、92、108、109及116 CYP3A4>20 μM: Compounds I-1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 , 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 40, 41, 42, 43, 44, 45, 47, 48, 49, 50, 52, 53 , 64, 65, 71, 86, 87, 88, 89, 90, 91, 92, 108, 109 and 116

CYP3A4>10μM：化合物I-51、55、56、57、61、66、68、69、70、78、79、80及81 CYP3A4>10 μM: Compounds I-51, 55, 56, 57, 61, 66, 68, 69, 70, 78, 79, 80 and 81

(測試實例6：波動艾姆斯測試) (Test Example 6: Volatility Ames Test)

將各20μL之冷凍儲存鼠傷寒沙門桿菌(Salmonella typhimurium)(TA98及TA100菌株)接種於10mL液體營養培養基(2.5%Oxoid營養培養液2號)中，且在震盪下在37℃下培育培養物10小時。 7.70mL TA98培養物經離心(2000×g，10分鐘)以移除培養基，且將細菌懸浮於7.70mL Micro F緩衝液(K2HPO4：3.5g/L，KH2PO4：1g/L，(NH4)2SO4：1g/L，二水合檸檬酸三鈉：0.25g/L，MgSO4．7H2O：0.1g/L)中，且將懸浮液添加至120mL Exposure培養基(MicroF緩衝液，含有生物素：8μg/mL，組胺酸：0.2μg/mL，葡萄糖：8mg/mL)。將3.42mL TA100培養物添加至130mL Exposure培養基以製備測試細菌溶液。將588μL測試細菌溶液(或在代謝活化系統之狀況下，498μl測試細菌溶液及90μL S9混合物之混合溶液)與各12μL之以下溶液混合：本發明化合物之DMSO溶液(自最大劑量50mg/mL以2至3倍比率之若干階段稀釋)；作為陰性對照之DMSO；關於無代謝活化系統之 TA98作為陽性對照之50μg/mL 4-硝基喹啉-1-氧化物DMSO溶液；關於無代謝活化系統之TA100作為陽性對照之0.25μg/mL 2-(2-呋喃基)-3-(5-硝基-2-呋喃基)丙烯醯胺DMSO溶液；關於有代謝活化系統之TA98作為陽性對照之40μg/mL 2-胺基蒽DMSO溶液；或關於有代謝活化系統之TA100作為陽性對照之20μg/mL 2-胺基蒽DMSO溶液。在震盪下在37℃下培育混合溶液90分鐘。將暴露於本發明化合物之460μL細菌溶液與2300μL Indicator培養基(Micro F緩衝液，含有生物素：8μg/mL，組胺酸：0.2μg/mL，葡萄糖：8mg/mL，Bromo Cresol Purple：37.5μg/mL)混合，將各50μL以48孔/劑量分配至微孔盤中，且在37℃下經受固定培養3天。含有已藉由基因編碼胺基酸(組胺酸)合成酶中之突變獲得增殖能力之細菌之孔的顏色由於pH變化自紫色變為黃色。計數在總48孔/劑量中之黃色孔之數目，且藉由與陰性對照組比較評估致突變性。(-)意謂致突變性為陰性且(+)意謂陽性。 Each 20 μL of frozen storage Salmonella typhimurium (TA98 and TA100 strain) was inoculated into 10 mL of liquid nutrient medium (2.5% Oxoid nutrient solution No. 2), and culture 10 was incubated at 37 ° C under shaking. hour. 7.70 mL of TA98 culture was centrifuged (2000 x g, 10 minutes) to remove the medium, and the bacteria were suspended in 7.70 mL of Micro F buffer (K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L) , (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate: 0.25 g / L, MgSO 4 .7H 2 O: 0.1 g / L), and the suspension was added to 120 mL Exposure medium (MicroF Buffer containing biotin: 8 μg/mL, histidine: 0.2 μg/mL, glucose: 8 mg/mL). 3.42 mL of TA100 culture was added to 130 mL of Exposure medium to prepare a test bacterial solution. 588 μL of the test bacterial solution (or a mixed solution of 498 μl of the test bacterial solution and 90 μL of the S9 mixture in the case of a metabolic activation system) was mixed with each of 12 μL of the following solution: a DMSO solution of the compound of the present invention (from a maximum dose of 50 mg/mL to 2 Dilution to several stages of a 3-fold ratio); DMSO as a negative control; 50 μg/mL 4-nitroquinoline-1-oxide DMSO solution as a positive control for TA98 without metabolic activation system; TA100 as a positive control of 0.25 μg/mL 2-(2-furyl)-3-(5-nitro-2-furanyl)propenylamine DMSO solution; 40 μg/ of TA98 with a metabolic activation system as a positive control mL 2 -amino guanidine DMSO solution; or 20 μg/mL 2-amino guanidine DMSO solution with TA100 as a positive control with a metabolic activation system. The mixed solution was incubated at 37 ° C for 90 minutes under shaking. 460 μL of the bacterial solution exposed to the compound of the present invention and 2300 μL of the Identify medium (Micro F buffer containing biotin: 8 μg/mL, histidine: 0.2 μg/mL, glucose: 8 mg/mL, Bromo Cresol Purple: 37.5 μg/ In mL), 50 μL of each was dispensed into a microplate at 48 well/dose, and subjected to fixed culture at 37 ° C for 3 days. The color of the pore containing the bacteria which have been proliferated by the mutation in the gene-encoded amino acid (histidine acid) synthetase changes from purple to yellow due to pH change. The number of yellow wells in the total of 48 wells/dose was counted and mutagenicity was assessed by comparison with the negative control group. (-) means that the mutagenicity is negative and (+) means positive.

(測試實例7：溶解度測試) (Test Example 7: Solubility Test)

在1%DMSO添加條件下測定各本發明化合物之溶解度。藉由DMSO製備10mmol/L化合物溶液，且分別添加2μL本發明化合物溶液至198μL JP第1流體(將水添加至2.0g氯化鈉及7.0mL氫氯酸中以達到1000mL)及JP第2流體(將1體積水添加至1體積3.40g二氫磷酸鉀及3.55g無水磷酸氫二鈉溶解於水中之溶液中以達到1000mL)。將混合物在25℃下保持靜置16小時或在室溫下震盪1小時，且將混合物真空過濾。用甲醇/水=1/1(v/v)或MeCN/MeOH/H2O(=1/1/2)將濾液稀釋十倍或一百倍，且以藉由絕對校準方法之LC/MS或固相萃取(SPE)/MS量測濾液中之化合物濃度。 The solubility of each of the present compounds was determined under the conditions of 1% DMSO addition. Prepare 10 mmol/L compound solution by DMSO, and add 2 μL of the compound solution of the present invention to 198 μL of JP first fluid (add water to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to reach 1000 mL) and JP second fluid (1 volume of water was added to a solution of 1 volume of 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous sodium hydrogen phosphate dissolved in water to reach 1000 mL). The mixture was allowed to stand at 25 ° C for 16 hours or at room temperature for 1 hour, and the mixture was vacuum filtered. Diluting the filtrate ten or one hundred times with methanol/water = 1/1 (v/v) or MeCN/MeOH/H 2 O (=1/1/2) with LC/MS by absolute calibration Or solid phase extraction (SPE) / MS to measure the concentration of the compound in the filtrate.

*1：在25℃下靜置16小時 *1: Allow to stand at 25 ° C for 16 hours

*2：在室溫下震盪1小時 *2: Shock for 1 hour at room temperature

(測試實例8：代謝穩定性測試) (Test Example 8: Metabolic Stability Test)

使用可商購的彙集人肝微粒體，本發明化合物經反應恆定時間，藉由比較反應樣品與未反應樣品計算殘留比例，進而評估肝臟中之代謝程度。 Using commercially available pooled human liver microsomes, the compound of the present invention was subjected to a reaction for a constant period of time, and the degree of metabolism in the liver was evaluated by comparing the reaction sample with the unreacted sample to calculate the residual ratio.

在含有0.5mg蛋白/毫升人肝微粒體之0.2mL緩衝液(50mmol/L Tris-HCl pH 7.4，150mmol/L氯化鉀，10mmol/L氯化鎂)中之1mmol/L NADPH存在下在37℃下進行反應(氧化反應)0分鐘或30分鐘。 在反應之後，將50μL反應溶液添加至100μL甲醇/乙腈=1/1(v/v)中，經混合且在3000轉/分鐘下離心15分鐘。藉由LC/MS/MS或固相萃取(SPE)/MS定量上清液中之本發明化合物，且計算在反應之後的本發明化合物之殘留量，使0分鐘反應時間處之化合物量為100%。 0.2 mL buffer (50 mmol/L) containing 0.5 mg protein/ml human liver microsomes The reaction (oxidation reaction) was carried out at 37 ° C for 0 minutes or 30 minutes in the presence of 1 mmol/L of NADPH in Tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/L magnesium chloride. After the reaction, 50 μL of the reaction solution was added to 100 μL of methanol/acetonitrile = 1/1 (v/v), mixed and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the supernatant was quantified by LC/MS/MS or solid phase extraction (SPE)/MS, and the residual amount of the compound of the present invention after the reaction was calculated so that the amount of the compound at the reaction time of 0 minutes was 100. %.

(測試實例9：hERG測試) (Test Example 9: hERG test)

出於評估心電圖QT間期延長之風險之目的，使用表現人類醚-a-go-go相關基因(hERG)通道之CHO細胞經研究對在本發明化合物之心室複極化過程中起重要作用之延遲整流K+電流(IKr)之效應。 For the purpose of assessing the risk of prolongation of the QT interval of the electrocardiogram, CHO cells expressing the human ether-a-go-go related gene (hERG) channel have been studied to play an important role in the ventricular repolarization of the compounds of the present invention. Delayed rectification of K+ current (I Kr ).

細胞藉由使用自動化膜片鉗系統(QPatch；Sophion Bioscience A/S)之全細胞膜片鉗方法保留於-80mV之薄膜電位處。在施加-50mV處之洩漏電位之後，記錄藉由+20mV處持續2秒之去極化脈衝刺激及-50mV處持續2秒之進一步複極化脈衝刺激誘發之IKr。 The cells were retained at a membrane potential of -80 mV by a whole cell patch clamp method using an automated patch clamp system (QPatch; Sophion Bioscience A/S). After applying a leakage potential at -50 mV, I Kr induced by a repolarization pulse stimulation at +20 mV for 2 seconds and further repolarization pulse stimulation at -50 mV for 2 seconds was recorded.

在產生之電流穩定之後，將其中本發明化合物已以目標濃度溶解之細胞外溶液(NaCl：145mmol/L，KCl：4mmol/L，CaCl2：2 mmol/L MgCl2：1mmol/L，1mmol/L，HEPES(4-(2-羥乙基)-1-哌乙磺酸：10mmol/L，葡萄糖：10mmol/L pH=7.4)在室溫條件下持續10分鐘塗覆至細胞。自記錄IKr，使用分析軟體(Falster Patch；Sophion Bioscience A/S)基於靜息薄膜電位處之電流值量測尾峰電流之絕對值。另外，計算在施用本發明化合物之前相對於尾峰電流之抑制%，且相比於施用媒劑之組(0.1%二甲亞碸溶液)以分析本發明化合物對IKr之影響。 After the generated current is stabilized, an extracellular solution in which the compound of the present invention has been dissolved at a target concentration (NaCl: 145 mmol/L, KCl: 4 mmol/L, CaCl 2 : 2 mmol/L MgCl 2 : 1 mmol/L, 1 mmol/) L, HEPES (4-(2-hydroxyethyl)-1-piperidyl Ethane sulfonic acid: 10 mmol/L, glucose: 10 mmol/L pH = 7.4) was applied to the cells at room temperature for 10 minutes. From the I Kr record, the analytical software (Falster Patch; Sophion Bioscience A/S) was used to measure the absolute value of the peak current based on the current value at the potential of the resting film. In addition, the % inhibition relative to the peak current before administration of the compound of the present invention was calculated, and the effect of the compound of the present invention on I Kr was analyzed as compared with the group of the administration vehicle (0.1% dimethyl sulfoxide solution).

(測試實例10：粉末溶解度測試) (Test Example 10: Powder Solubility Test)

將適當量之本發明化合物放入適當容器中。將200μL JP第1流體(將水添加至2.0g氯化鈉及7.0mL氫氯酸中以達到1000mL)、200μL JP第2流體(將1體積水添加至1體積3.40g二氫磷酸鉀及3.55g無水 磷酸氫二鈉溶解於水中之溶液中以達到1000mL)及200μL含有20mmol/L牛磺膽酸鈉(TCA)之JP第2流體(TCA 1.08g，及JP第2流體以製得100mL)添加至對應容器中。當總量之本發明化合物在添加測試流體之後溶解時，按需要添加化合物。將容器密封，且在37℃下震盪1小時。過濾混合物，且將100μL之甲醇添加至各濾液(100μL)中以使得濾液經兩倍稀釋。稀釋比率可在必要時改變。在證實稀釋溶液中不存在泡沫及沈澱之後，將容器密封且震盪。藉由HPLC以絕對校準方法進行定量。 A suitable amount of the compound of the invention is placed in a suitable container. 200 μL of JP first fluid (water added to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to reach 1000 mL), 200 μL of JP second fluid (add 1 volume of water to 1 volume of 3.40 g of potassium dihydrogen phosphate and 3.55) g without water A solution of disodium hydrogen phosphate dissolved in water to achieve 1000 mL) and 200 μL of JP second fluid (TCA 1.08 g, and JP second fluid to obtain 100 mL) containing 20 mmol/L sodium taurocholate (TCA) were added to Corresponding to the container. When the total amount of the compound of the invention is dissolved after the addition of the test fluid, the compound is added as needed. The vessel was sealed and shaken at 37 ° C for 1 hour. The mixture was filtered, and 100 μL of methanol was added to each filtrate (100 μL) so that the filtrate was diluted twice. The dilution ratio can be changed as necessary. After confirming the absence of foam and precipitation in the dilute solution, the container was sealed and shaken. Quantification was performed by HPLC using an absolute calibration method.

(測試實例11：藥物動力學研究) (Test Example 11: Pharmacokinetic Study)

用於口服吸收之研究的材料及方法 Materials and methods for oral absorption studies

(1)動物：小鼠或大鼠 (1) Animals: mice or rats

(2)飼養條件：小鼠或大鼠允許自由接近自來水及固體食物。 (2) Feeding conditions: The mouse or rat is allowed to freely access tap water and solid food.

(3)劑量及分組：以預定劑量經口或靜脈內投與；分組如下(劑量取決於化合物) (3) Dosage and grouping: administered orally or intravenously at a predetermined dose; grouped as follows (dose depending on compound)

經口投與：1至30mg/kg(n=2至3) Oral administration: 1 to 30 mg/kg (n=2 to 3)

靜脈內投與：0.5至10mg/kg(n=2至3) Intravenous administration: 0.5 to 10 mg/kg (n=2 to 3)

(4)給藥調配物：對於經口投與，以溶液或懸浮液狀態；對於靜脈內投與，以溶解狀態 (4) Administration formulation: for oral administration, in the form of a solution or suspension; for intravenous administration, in a dissolved state

(5)給藥方法：在經口投與中，使用附接可撓性飼管之注射器強制投與；在靜脈內投與中，使用附接有針之注射器自尾側靜脈投與。 (5) Administration method: In oral administration, it is forcibly administered using a syringe attached with a flexible feeding tube; in intravenous administration, it is administered from the caudal vein using a syringe to which a needle is attached.

(6)評估項目：在預定時間採集血液，且藉由LC/MS/MS量測本發明化合物之血漿濃度 (6) Evaluation item: blood is collected at a predetermined time, and the plasma concentration of the compound of the present invention is measured by LC/MS/MS

(7)統計分析：關於本發明化合物之血漿濃度之轉變，藉由非線性最小平方程式WinNonlin(註冊商標)計算血漿濃度-時間曲線下面積(AUC)，且自經口投與組及靜脈內投與組之AUC計算本發明化合物之生物可用性(BA) (7) Statistical analysis: Regarding the transition of the plasma concentration of the compound of the present invention, the area under the plasma concentration-time curve (AUC) was calculated by the nonlinear least squares program WinNonlin (registered trademark), and was administered from the oral administration group and intravenously. Administration of the group's AUC to calculate the bioavailability of the compounds of the invention (BA)

(測試實例12：腦分佈研究) (Test Example 12: Brain Distribution Study)

以0.5mg/mL/kg劑量向大鼠靜脈內投與本發明化合物。30分鐘後，在異氟醚麻醉下自腹部主動脈抽取所有血液以自放血死亡。 The compound of the present invention was intravenously administered to rats at a dose of 0.5 mg/mL/kg. After 30 minutes, all blood was drawn from the abdominal aorta under isoflurane anesthesia to die from bloodletting.

剜出腦且藉由蒸餾水製備其20%至25%均質物。 The brain was extracted and its 20% to 25% homogenate was prepared by distilled water.

獲得之血液在離心之後用作血漿。將對照血漿以1：1添加至腦樣品。將對照腦均質物以1：1添加至血漿樣品。使用LC/MS/MS量測各樣品。獲得之面積比(腦/血漿)用於腦Kp值。 The obtained blood is used as plasma after centrifugation. Control plasma was added to brain samples at 1:1. Control brain homogenates were added to plasma samples at 1:1. Each sample was measured using LC/MS/MS. The area ratio obtained (brain/plasma) was used for brain Kp values.

(測試實例13：艾姆斯測試) (Test Example 13: Ames Test)

藉由使用沙門桿菌(鼠傷寒沙門桿菌)TA 98、TA100、TA1535及TA1537及大腸桿菌WP2uvrA作為預培育方法中之具有或不具有代謝活化之測試菌株以檢查本發明化合物存在或不存在基因致突變性來進行艾姆斯測試。 Examination of the presence or absence of gene mutagenesis of a compound of the invention by using Salmonella typhimurium (S. typhimurium) TA 98, TA100, TA1535 and TA1537 and E. coli WP2uvrA as test strains with or without metabolic activation in a pre-incubation method Sex to test the Ames.

(測試實例14：P-gp受質測試) (Test Example 14: P-gp quality test)

1.細胞株： 1. Cell line:

a. MDR1/LLC-PK1(Becton Dickinson) a. MDR1/LLC-PK1 (Becton Dickinson)

b. LLC-PK1(Becton Dickinson) b. LLC-PK1 (Becton Dickinson)

2.參考受質： 2. Reference quality:

a.地高辛(Digoxin)(2μM) a. Digoxin (2μM)

方法及程序 Method and procedure

1.在37℃下在5%CO2/95%O2氣體下於培養基A(補充有10%FBS(Invitrogen)、健大黴素(gentamycin)(0.05mg/mL，Invitrogen)及潮黴素B(100μg/mL，Invitrogen)之培養基199(Invitrogen))中常規地培養表現MDR1之LLC-PK1細胞及其親本細胞。對於輸送實驗，將此等細胞以1.4×104個細胞/***物之密度接種於Transwell(註冊商標)***物(96孔，孔徑：0.4μm，Coaster)上且將培養基B(補充有10%FBS及0.05mg/mL之健大黴素之培養基199)添加至給料盤。在CO2恆溫箱(5%CO2/95%O2氣體，37℃)中培育此等細胞且在接種之後每隔48-72 h替換頂端及底外側培養基。此等細胞在接種後4與6天之間使用。 1. At medium temperature A at 37 ° C under 5% CO 2 /95% O 2 gas (supplemented with 10% FBS (Invitrogen), gentamycin (0.05 mg/mL, Invitrogen) and hygromycin LLC-PK1 cells expressing MDR1 and their parental cells were routinely cultured in medium 199 (Invitrogen) of B (100 μg/mL, Invitrogen). For delivery experiments, these cells were seeded at a density of 1.4×10 4 cells/insert in Transwell (registered trademark) insert (96 well, pore size: 0.4 μm, Coaster) and medium B (supplemented with 10%) FBS and 0.05 mg/mL of gentamicin medium 199) were added to the feed pan. The cells were incubated in a CO 2 incubator (5% CO 2 /95% O 2 gas, 37 ° C) and the apical and basolateral media were replaced every 48-72 h after inoculation. These cells were used between 4 and 6 days after inoculation.

2.藉由抽吸移除接種有表現MDR1之細胞或親本細胞之培養***物中之培養基且藉由HBSS沖洗。以含有參考受質及本發明之輸送緩衝液替換頂側(140μL)或底外側(175μL)，接著收集供體側之輸送緩衝液之等分試樣(50μL)以評估參考受質及本發明之初始濃度。在37。℃下培育所設計時間之後，收集供體及接受者側之輸送緩衝液之等分試樣(50μL)。重複兩次或重複三次進行分析。 2. The medium inoculated in the culture insert inoculated with cells expressing MDR1 or parental cells was removed by aspiration and rinsed by HBSS. The top side (140 μL) or the bottom side (175 μL) was replaced with a reference buffer containing the reference substrate and the present invention, followed by collecting an aliquot (50 μL) of the donor side delivery buffer to evaluate the reference substrate and the present invention. The initial concentration. At 37. After the design time was incubated at ° C, an aliquot (50 μL) of the delivery buffer on the donor and recipient sides was collected. The analysis was repeated twice or three times.

3.藉由LC/MS/MS定量等分試樣中之參考受質及本發明。 3. Quantitative reference to the reference in the aliquot by LC/MS/MS and the present invention.

計算 Calculation

測定跨越單層表現MDR1之細胞及親本細胞之滲透量，且使用Excel 2003自以下方程式計算滲透係數(Pe)：Pe(cm/sec)=滲透量(pmol)/細胞膜面積(cm2)/初始濃度(nM)/培育時間(sec) The amount of permeation of cells expressing MDR1 across the monolayer and the parental cells was determined, and the permeability coefficient (Pe) was calculated from the following equation using Excel 2003: Pe (cm/sec) = permeation amount (pmol) / cell membrane area (cm 2 ) / Initial concentration (nM) / incubation time (sec)

其中，滲透量計算自物質在培育定義時間(sec)之後的滲透濃度(nM，接受者側之濃度)乘以體積(mL)且使用之細胞膜面積為0.1433(cm2)。 Here, the amount of permeation was calculated from the osmotic concentration (nM, concentration on the recipient side) of the substance after the culture definition time (sec) multiplied by the volume (mL) and the cell membrane area used was 0.1433 (cm 2 ).

使用以下方程式計算流出比率：流出比率=底外側比頂端Pe/頂端比底外側Pe The outflow ratio is calculated using the following equation: outflow ratio = bottom outer side than top end Pe / top end than bottom outer side Pe

使用以下方程式計算淨通量：淨通量=表現MDR1之細胞中之流出比率/親本細胞中之流出比率 Calculate the net flux using the following equation: net flux = outflow ratio in cells expressing MDR1 / outflow ratio in parental cells

(測試實例15：對P-gp輸送之抑制效應) (Test Example 15: Inhibition effect on P-gp transport) 材料 material

1.細胞株： 1. Cell line:

a. MDR1/LLC-PK1(Becton Dickinson) a. MDR1/LLC-PK1 (Becton Dickinson)

b. LLC-PK1(Becton Dickinson) b. LLC-PK1 (Becton Dickinson)

2.參考受質： 2. Reference quality:

a.[3H]地高辛(1μM) a.[ 3 H] Digoxin (1 μM)

b.[14C]甘露醇(5μM) b. [ 14 C]mannitol (5 μM)

3.參考抑制劑： 3. Reference inhibitor:

環孢素A(10μM) Cyclosporin A (10 μM)

方法及程序 Method and procedure

1.在37℃下在5%CO2/95%O2氣體下於培養基A(補充有10%FBS(Invitrogen)、健大黴素(gentamycin)(0.05mg/mL，Invitrogen)及潮黴素B(100μg/mL，Invitrogen)之培養基199(Invitrogen))中常規地培養表現MDR1之LLC-PK1細胞及其親本細胞。對於輸送實驗，將此等細胞以4×104個細胞/***物之密度接種於Transwell(註冊商標)***物(24孔，孔徑：0.4μm，Coaster)上且將培養基B(補充有10%FBS及0.05mg/mL之健大黴素之培養基199)添加至給料盤。在CO2恆溫箱(5%CO2/95%O2氣體，37℃)中培育此等細胞且在接種之後每隔48-72h替換頂端及底外側培養基。此等細胞在接種後6與9天之間使用。 1. At medium temperature A at 37 ° C under 5% CO 2 /95% O 2 gas (supplemented with 10% FBS (Invitrogen), gentamycin (0.05 mg/mL, Invitrogen) and hygromycin LLC-PK1 cells expressing MDR1 and their parental cells were routinely cultured in medium 199 (Invitrogen) of B (100 μg/mL, Invitrogen). For delivery experiments, these cells were seeded at a density of 4 x 10 4 cells/insert in Transwell (registered trademark) insert (24 well, pore size: 0.4 μm, Coaster) and medium B (supplemented with 10%) FBS and 0.05 mg/mL of gentamicin medium 199) were added to the feed pan. These cells were incubated in a CO 2 incubator (5% CO 2 /95% O 2 gas, 37 ° C) and the apical and basolateral media were replaced every 48-72 h after inoculation. These cells were used between 6 and 9 days after inoculation.

2.藉由抽吸移除接種有表現MDR1之細胞或親本細胞之培養***物中之培養基且藉由HBSS沖洗。以具有或不具有本發明化合物的含參考受質之輸送緩衝液替換頂側(250μL)或底外側(850μL)，接著收集供體側之輸送緩衝液之等分試樣(50μL)以評估參考受質之初始濃度。在37℃下培育所設計時間之後，收集供體及接受者側之輸送緩衝液之等分試樣(50μL)。重複三次進行分析。 2. The medium inoculated in the culture insert inoculated with cells expressing MDR1 or parental cells was removed by aspiration and rinsed by HBSS. Replace the top side (250 μL) or the bottom side (850 μL) with a reference buffer containing the reference compound with or without the compound of the invention, and then collect an aliquot (50 μL) of the donor buffer on the donor side to evaluate the reference. The initial concentration of the substrate. After incubation for a design period at 37 ° C, aliquots (50 μL) of the delivery buffer on the donor and recipient sides were collected. The analysis was repeated three times.

3.將輸送緩衝液之等分試樣(50μL)與5mL閃爍混合液混合，且使用液體閃爍計數器量測放射性。 3. Aliquots (50 [mu]L) of delivery buffer were mixed with 5 mL scintillation cocktail and radioactivity was measured using a liquid scintillation counter.

計算 Calculation

測定跨越單層表現MDR1之細胞及親本細胞之滲透量，且使用Excel 2003自以下方程式計算滲透係數(Pe)：Pe(cm/sec)=滲透量(pmol)/細胞膜面積(cm2)/初始濃度(nM)/培育時間(sec) The amount of permeation of cells expressing MDR1 across the monolayer and the parental cells was determined, and the permeability coefficient (Pe) was calculated from the following equation using Excel 2003: Pe (cm/sec) = permeation amount (pmol) / cell membrane area (cm 2 ) / Initial concentration (nM) / incubation time (sec)

其中，滲透量計算自物質在培育定義時間(sec)之後的滲透濃度(nM，接受者側之濃度)乘以體積(mL)且使用之細胞膜面積為0.33(cm2)。 Here, the amount of permeation was calculated from the osmotic concentration (nM, concentration on the recipient side) of the substance after the culture definition time (sec) multiplied by the volume (mL) and the cell membrane area used was 0.33 (cm 2 ).

將使用以下方程式計算流出比率：流出比率=底外側比頂端Pe/頂端比底外側Pe The outflow ratio will be calculated using the following equation: Outflow ratio = bottom outer side than top end Pe / top end than bottom outer side Pe

使用以下方程式計算淨通量：淨通量=表現MDR1之細胞中之流出比率/親本細胞中之流出比率 Calculate the net flux using the following equation: net flux = outflow ratio in cells expressing MDR1 / outflow ratio in parental cells

以在存在本發明化合物之情況下之參考化合物與在不存在本發明化合物之情況下之參考化合物之淨流出比計算對照物之百分比。 The percentage of the control is calculated as the net outflow ratio of the reference compound in the presence of the compound of the invention to the reference compound in the absence of the compound of the invention.

使用WinNonlin(註冊商標)藥物動力學軟體建模程式計算IC50值。 IC 50 values are calculated using the WinNonlin (registered trademark) Kinetic modeling software programs medicament.

(測試實例16：使用mdr1a(-/-)B6小鼠之P-gp受質測試) (Test Example 16: P-gp-substance test using mdr1a(-/-)B6 mice)

材料 material

動物：mdr1a(-/-)B6小鼠(KO小鼠)或C57BL/6J小鼠(野生型小鼠)方法及程序 Animal: mdr1a (-/-) B6 mouse (KO mouse) or C57BL/6J mouse (wild type mouse) method and procedure

1.動物可在給予本發明化合物之前餵食。 1. Animals can be fed prior to administration of a compound of the invention.

2.各時間點向三隻動物給予本發明化合物且在給藥之後的選擇時間點(例如15分鐘、30分鐘、1小時、2小時、4小時、6小時、8小時或24小時)移除血液及腦樣品。經由乾血採集用含有抗凝血劑(EDTA及肝素)之注射器採集血液(0.3-0.7mL)。緊接著將血液及組織(例如腦)樣品置於融冰上。 2. Administration of a compound of the invention to three animals at each time point and removal at a selected time point (eg, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, or 24 hours) after administration. Blood and brain samples. Blood (0.3-0.7 mL) was collected via a dry blood collection using a syringe containing an anticoagulant (EDTA and heparin). The blood and tissue (eg, brain) samples are then placed on the melted ice.

3.血液樣品經離心(1780×g，持續10分鐘)以移除細胞以獲得血漿。隨後，將血漿樣品轉移至清潔導管中且儲存於-70℃冷凍器中直至分析。 3. The blood sample was centrifuged (1780 x g for 10 minutes) to remove the cells to obtain plasma. Subsequently, plasma samples were transferred to a cleansing catheter and stored in a -70 °C freezer until analysis.

4.組織(例如腦)樣品以組織重量與蒸餾水之ml之1：3之比均質化且轉移至清潔導管中且儲存於-70℃冷凍器中直至分析。 4. Tissue (eg, brain) samples were homogenized at a 1:3 ratio of tissue weight to ml of distilled water and transferred to a cleansing catheter and stored in a -70 °C freezer until analysis.

5.使用蛋白沈澱製備血漿及組織(例如腦)樣品且藉由LC/MS/MS分析。分析方法藉由包括以空白血漿或腦樣品及已知量之分析物構築之標準曲線校準。包括品質控制樣品以監視方法之精確性及精密度。 5. Plasma and tissue (eg, brain) samples were prepared using protein precipitation and analyzed by LC/MS/MS. Analytical methods are calibrated by including a standard curve constructed from blank plasma or brain samples and known amounts of analyte. Quality control samples are included to monitor the accuracy and precision of the method.

6.將血漿及腦濃度值(ng/mL及ng/g)引入至用於計算藥物動力學參數之適當數學工具中。常用平台為WinNonlin(註冊商標)藥物動力學軟體建模程式。 6. Plasma and brain concentration values (ng/mL and ng/g) were introduced into appropriate mathematical tools for calculating pharmacokinetic parameters. The commonly used platform is the WinNonlin (registered trademark) pharmacokinetic software modeling program.

計算 Calculation

Kp；組織與血漿濃度比率 Kp; tissue to plasma concentration ratio

Kp比率=KO小鼠中之Kp/野生型小鼠中之Kp Kp ratio = Kp in Kp/wild type mice in KO mice

KO之AUC組織/AUC血漿與野生型AUC組織/AUC血漿之比率 Ratio of KO AUC tissue/AUC plasma to wild-type AUC tissue/AUC plasma

={AUC組織/AUC血漿(KO小鼠)}/{AUC組織/AUC血漿(野生型小鼠)} ={AUC tissue/AUC plasma (KO mice)}/{AUC tissue/AUC plasma (wild type mouse)}

(測試實例17：麻醉天竺鼠心血管研究) (Test Example 17: Anesthetic guinea pig cardiovascular study)

動物種類：天竺鼠(Slc：Hartley，4-6週齡，雄性)，N=4 Animal species: guinea pig (Slc: Hartley, 4-6 weeks old, male), N=4

研究設計：劑量：3、10及30mg/kg(原則上) Study design: Dosage: 3, 10 and 30 mg/kg (in principle)

(累積地投與本發明化合物) (accumulatively administering the compound of the present invention)

配方：媒劑之組成；二甲基乙醯胺(DMA)：聚乙二醇400(PEG400)：蒸餾水(D.W.)=1：7：2(原則上)。 Formulation: composition of the vehicle; dimethylacetamide (DMA): polyethylene glycol 400 (PEG400): distilled water (D.W.) = 1:7:2 (in principle).

本發明化合物藉由DMA溶解，接著添加PEG400及D.W.。最後，製備1.5、5及15mg/mL溶液。 The compound of the invention was dissolved by DMA followed by the addition of PEG 400 and D.W. Finally, 1.5, 5 and 15 mg/mL solutions were prepared.

給藥途徑及時程：靜脈內輸注，持續10分鐘(2mL/kg)。 Route of administration: Time course: intravenous infusion for 10 minutes (2mL/kg).

0至10分鐘：3mg/kg，30至40分鐘：10mg/kg，60至70分鐘：30mg/kg 0 to 10 minutes: 3 mg/kg, 30 to 40 minutes: 10 mg/kg, 60 to 70 minutes: 30 mg/kg

藉由與上文相同之時程投與媒劑。 The vehicle is administered by the same time course as above.

組之組成：媒劑組及本發明化合物組(4隻天竺鼠/組)。評估方法： Composition of the group: vehicle group and compound group of the invention (4 guinea pigs/group). evaluation method:

評估項目：平均血壓[mmHg]、心率(來源於血壓波形[跳動/分鐘])、QTc(ms)及毒物動態學。 Assessment items: mean blood pressure [mmHg], heart rate (derived from blood pressure waveform [jitter/minute]), QTc (ms), and toxic dynamics.

實驗程序：藉由胺基甲酸酯(1.4g/kg，腹膜內)麻醉天竺鼠，且將聚乙烯導 管***頸動脈(用於量測血壓及血液取樣)及頸靜脈(用於輸注測試化合物)中。在皮下附接電極(Lead 2)。使用PowerLab(註冊商標)系統(ADInstruments)量測血壓、心率及心電圖(ECG)。 Experimental procedure: guinea pigs were anesthetized with urethane (1.4 g/kg, ip) and the polyethylene was guided The tube was inserted into the carotid artery (for blood pressure and blood sampling) and the jugular vein (for infusion of test compound). The electrode (Lead 2) is attached subcutaneously. Blood pressure, heart rate, and electrocardiogram (ECG) were measured using the PowerLab (registered trademark) system (ADInstruments).

毒物動態學： 用含有肝素鈉之注射器自頸動脈抽取大致0.3mL血液(大致150μL呈血漿形式)且在各評估點立即藉由冰冷卻。藉由離心(4℃，10000轉/分鐘，9300×g，2分鐘)獲得血漿樣品。在冰上或在4℃下進行分離血漿之程序。獲得之血漿(TK樣品)儲存於深度冷凍器(設定溫度：-80℃)中。 Toxic dynamics: Approximately 0.3 mL of blood (approximately 150 μL in plasma form) was drawn from the carotid artery with a syringe containing sodium heparin and immediately cooled by ice at each evaluation point. Plasma samples were obtained by centrifugation (4 ° C, 10,000 rpm, 9300 x g, 2 minutes). The procedure for separating plasma was performed on ice or at 4 °C. The obtained plasma (TK sample) was stored in a deep freezer (set temperature: -80 ° C).

分析方法：在各評估時間點以30秒時段對平均血壓及心率平均化。以評估時間點之10秒連續跳動之平均波形形式產生ECG參數(QT時間間隔[ms]及QTc。使用PowerLab(註冊商標)系統計算QTc[腓特烈西亞公式(Fridericia's formula)；QTc=QT/(RR)1/3]。關於所有四隻動物之所有ECG記錄(自給藥前0.5小時至實驗結束)以肉眼評估心律不整之發生率。 Analytical method: Average blood pressure and heart rate were averaged over a 30 second period at each evaluation time point. ECG parameters (QT time interval [ms] and QTc are generated in the form of an average waveform of 10 seconds of continuous jitter at the evaluation time point. QTc is calculated using the PowerLab (registered trademark) system [Fridericia's formula; QTc=QT/ (RR) 1/3] The incidence of arrhythmia was visually assessed with respect to all ECG records for all four animals (0.5 hours prior to dosing to the end of the experiment).

評估時間點： 第一次給藥之前(給藥前)及在第一次給藥之後10、25、40、55、70及85分鐘。 Evaluation time point: Before the first dose (before administration) and 10, 25, 40, 55, 70 and 85 minutes after the first dose.

QTc之資料分析： 計算QTc自給藥前值之百分比變化(%)(將給藥前值視為100%)。將相對QTc相比於相同評估點之媒劑值。 QTc data analysis: The percentage change (%) of QTc from the pre-dose value was calculated (the pre-dose value was regarded as 100%). The relative QTc is compared to the media value of the same evaluation point.

調配物實例 Formulation instance

以下調配物實例僅為例示性的且並不意欲限制本發明之範疇。調配物實例1：錠劑 The following examples of formulations are merely illustrative and are not intended to limit the scope of the invention. Formulation Example 1: Lozenges

硬脂酸鈣 3mg Calcium stearate 3mg

除硬脂酸鈣之外的所有以上成分經均勻混合。隨後將混合物壓碎、粒化及乾燥以獲得適合之粒度。隨後，將硬脂酸鈣添加至顆粒中。最後，在壓縮力下進行製錠。 All of the above ingredients except calcium stearate were uniformly mixed. The mixture is then crushed, granulated and dried to obtain a suitable particle size. Subsequently, calcium stearate is added to the granules. Finally, the ingot is produced under a compressive force.

調配物實例2：膠囊 Formulation Example 2: Capsules

均勻混合以上成分以獲得粉末或精細顆粒，接著將所獲得之混合物填充於膠囊中。 The above ingredients are uniformly mixed to obtain a powder or fine particles, and then the obtained mixture is filled in a capsule.

調配物實例3：顆粒 Formulation Example 3: Granules

在均勻混合以上成分之後，壓縮混合物。將壓縮物壓碎粒化及篩分以獲得適合之粒度。 After uniformly mixing the above ingredients, the mixture was compressed. The compact is crushed and sieved to obtain a suitable particle size.

調配物實例4：口腔崩解錠 Formulation Example 4: Oral disintegration ingot

將本發明化合物及結晶纖維素混合、粒化且製錠，得到口服崩解錠。 The compound of the present invention and crystalline cellulose are mixed, granulated, and tableted to obtain an orally disintegrating ingot.

調配物實例5：乾糖漿 Formulation Example 5: Dry syrup

將本發明化合物及乳糖混合、壓碎、粒化及篩分，得到適合尺寸之乾糖漿。 The compound of the invention and the lactose are mixed, crushed, granulated and sieved to obtain a dry syrup of suitable size.

調配物實例6：注射劑 Formulation Example 6: Injection

將本發明化合物及磷酸鹽緩衝液混合，得到注射劑。 The compound of the present invention and a phosphate buffer are mixed to obtain an injection.

調配物實例7：輸注液 Formulation Example 7: Infusion

將本發明化合物及磷酸鹽緩衝液混合，得到注射劑。 The compound of the present invention and a phosphate buffer are mixed to obtain an injection.

調配物實例8：吸入劑 Formulation Example 8: Inhalation

將本發明化合物及乳糖混合及精細壓碎，得到吸入劑。 The compound of the present invention and lactose are mixed and finely crushed to obtain an inhalant.

調配物實例9：軟膏 Formulation Example 9: Ointment

將本發明化合物及礦脂混合，得到軟膏。 The compound of the present invention and petrolatum are mixed to obtain an ointment.

調配物實例10：貼片 Formulation Example 10: Patch

將本發明化合物及諸如黏著硬膏劑或其類似者之鹼混合，得到貼片。 The compound of the present invention and a base such as an adhesive plaster or the like are mixed to obtain a patch.

[工業實用性] [Industrial Applicability]

本發明化合物可為適用作治療或預防由澱粉狀蛋白β蛋白之產生、分泌及/或沈積所誘發之疾病之藥劑的藥物。 The compound of the present invention may be a drug which is useful as an agent for treating or preventing a disease induced by the production, secretion and/or deposition of amyloid β protein.

Claims (19)

一種式(I)化合物， 其中X為-S-或-O-，(i)若X為-S-，則R3a為烷基、鹵烷基、羥烷基或烷氧基烷基R2a為鹵素、烷氧基或鹵烷氧基，且當R3a為鹵烷基時，R2a可為烷基，R2b為H，R2a及R2b連同其所連接之碳原子可形成經取代環烷，當R2a及R2b連同其所連接之碳原子可形成經取代環烷時，R3a可為H，(ii)若X為-O-，則R3a為視情況經選自烷氧基及環烷基之一或多者取代之鹵烷基，或經選自鹵素之一或多者取代之環烷基，R2a為H、鹵素、烷基、烷氧基或鹵烷氧基，R2b為H，R2a及R2b連同其所連接之碳原子可形成經取代環烷，當R2a及R2b連同其所連接之碳原子可形成經取代環烷時，R3a可為H或烷基，R3b為H或烷基， 環A為經取代或未經取代之芳族碳環、經取代或未經取代之非芳族碳環、經取代或未經取代之芳族雜環或經取代或未經取代之非芳族雜環，環B為經取代或未經取代之芳族碳環、經取代或未經取代之非芳族碳環、經取代或未經取代之芳族雜環或經取代或未經取代之非芳族雜環，R1為經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基或經取代或未經取代之環烷基，R5為鹵素或經取代或未經取代之烷基，n為0至2之整數，其限制條件為排除以下化合物：(1)其中X為-O-、R3a為CH2F或CF3、R3b為H、R2a為H或F且R2b為H之化合物，(2)其中X為-O-、R3a為CHF2、R3b為H、R2a為OMe且R2b為H之化合物，(3)以下化合物： 或其醫藥學上可接受之鹽。 a compound of formula (I), Wherein X is -S- or -O-, (i) if X is -S-, then R 3a is alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl R 2a is halo, alkoxy or Haloalkoxy, and when R 3a is haloalkyl, R 2a can be alkyl, R 2b is H, and R 2a and R 2b together with the carbon atom to which they are attached can form substituted naphthenes, when R 2a and When R 2b together with the carbon atom to which it is attached may form a substituted cycloalkane, R 3a may be H, (ii) if X is -O-, then R 3a is optionally selected from the group consisting of an alkoxy group and a cycloalkyl group. One or more substituted haloalkyl groups, or a cycloalkyl group substituted by one or more halogens, R 2a is H, halogen, alkyl, alkoxy or haloalkoxy, and R 2b is H, R 2a and R 2b together with the carbon atom to which they are attached may form a substituted cycloalkane, and when R 2a and R 2b together with the carbon atom to which they are attached may form a substituted cycloalkane, R 3a may be H or an alkyl group, R 3b is H or an alkyl group, Ring A is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted non-aromatic group Heterocyclic ring, ring B is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted a non-aromatic heterocyclic ring, R 1 being a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group or a substituted or unsubstituted cycloalkyl group, R 5 is halogen or substituted or unsubstituted alkyl, and n is an integer of 0 to 2, with the proviso that the following compounds are excluded: (1) wherein X is -O-, and R 3a is CH 2 F or CF 3 , R 3b is H, R 2a is H or F and R 2b is H, (2) wherein X is -O-, R 3a is CHF 2 , R 3b is H, R 2a is OMe and R 2b is H Compound, (3) the following compounds: Or a pharmaceutically acceptable salt thereof. 如請求項1之化合物，其中X為-O-，或其醫藥學上可接受之鹽。 The compound of claim 1, wherein X is -O-, or a pharmaceutically acceptable salt thereof. 如請求項2之化合物，其中R3a為CH2F、CHF2、CF3、CH(F)CH3或CF2CH3，且R3b為H或CH3，或其醫藥學上可接受之鹽。 The compound of claim 2, wherein R 3a is CH 2 F, CHF 2 , CF 3 , CH(F)CH 3 or CF 2 CH 3 , and R 3b is H or CH 3 , or a pharmaceutically acceptable compound thereof salt. 如請求項2或3之化合物，其中R2a為H、F、CH3、OCH3或OCH2CF3，或其醫藥學上可接受之鹽。 The compound of claim 2 or 3, wherein R 2a is H, F, CH 3 , OCH 3 or OCH 2 CF 3 , or a pharmaceutically acceptable salt thereof. 如請求項2或3之化合物，其中R2a為H、鹵素或烷基，R2b為H，且R3a為CHF2、CH(F)CH3或CF2CH3，或其醫藥學上可接受之鹽。 The compound of claim 2 or 3, wherein R 2a is H, halogen or alkyl, R 2b is H, and R 3a is CHF 2 , CH(F)CH 3 or CF 2 CH 3 , or pharmaceutically acceptable thereof Accept the salt. 如請求項2之化合物，其中R2a為H或鹵素，R2b為H，R3a為CH2F或CF3，R3b為烷基，且R1為未經取代烷基，或其醫藥學上可接受之鹽。 The compound of claim 2, wherein R 2a is H or halogen, R 2b is H, R 3a is CH 2 F or CF 3 , R 3b is alkyl, and R 1 is unsubstituted alkyl, or a medicinal thereof Acceptable salt. 如請求項2或3之化合物，其中R2a為烷基、烷氧基或鹵烷氧基，或其醫藥學上可接受之鹽。 A compound according to claim 2 or 3, wherein R 2a is an alkyl group, an alkoxy group or a haloalkoxy group, or a pharmaceutically acceptable salt thereof. 如請求項2之化合物，其中： R5為鹵素且n為1或2，或其醫藥學上可接受之鹽。 The compound of claim 2, wherein: R 5 is a halogen and n is 1 or 2, or a pharmaceutically acceptable salt thereof. 如請求項2之化合物，其中R3a為經烷氧基或環烷基取代之鹵烷基，或其醫藥學上可接受之鹽。 A compound according to claim 2, wherein R 3a is a haloalkyl group substituted by an alkoxy group or a cycloalkyl group, or a pharmaceutically acceptable salt thereof. 如請求項1之化合物，其中X為-S-，R2a為鹵素或烷氧基，R2b為H，R3a為烷基、鹵烷基、羥烷基或烷氧基烷基，且R3b為H，或其醫藥學上可接受之鹽。 The compound of claim 1, wherein X is -S-, R 2a is halogen or alkoxy, R 2b is H, and R 3a is alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl, and R 3b is H, or a pharmaceutically acceptable salt thereof. 如請求項1之化合物，其中X為-S-，R2a為F，R2b為H，R3a為CH3或CH2F，且R3b為H，或其醫藥學上可接受之鹽。 The compound of claim 1, wherein X is -S-, R 2a is F, R 2b is H, R 3a is CH 3 or CH 2 F, and R 3b is H, or a pharmaceutically acceptable salt thereof. 如請求項1之化合物，其中R2a及R2b連同其所連接之碳原子形成 經鹵素取代之環烷，R3a為H或烷基，或其醫藥學上可接受之鹽。 The compound of claim 1, wherein R 2a and R 2b together with the carbon atom to which they are attached form a halogen-substituted cycloalkane, and R 3a is H or an alkyl group, or a pharmaceutically acceptable salt thereof. 如請求項1、2及10中任一項之化合物，其中R1為烷基，或其醫藥學上可接受之鹽。 The compound of any one of claims 1, 2 and 10, wherein R 1 is an alkyl group, or a pharmaceutically acceptable salt thereof. 如請求項1、2及10中任一項之化合物，其中環A為 其中R4為H或鹵素，且-Z=為-CH=或-N=，或其醫藥學上可接受之鹽。 The compound of any one of claims 1, 2, and 10, wherein ring A is Wherein R 4 is H or halogen, and -Z = is -CH= or -N=, or a pharmaceutically acceptable salt thereof. 如請求項14之化合物，其中R4為鹵素且-Z=為-CH=，或其醫藥學上可接受之鹽。 The compound of claim 14, wherein R 4 is halogen and -Z = is -CH=, or a pharmaceutically acceptable salt thereof. 如請求項1、2及10中任一項之化合物，其中環B為經取代或未經取代之吡啶、經取代或未經取代之吡、經取代或未經取代之嘧啶、經取代或未經取代之噠或經取代或未經取代之唑，或其醫藥學上可接受之鹽。 The compound of any one of claims 1, 2, and 10, wherein ring B is substituted or unsubstituted pyridine, substituted or unsubstituted pyridyl Substituted or unsubstituted pyrimidine, substituted or unsubstituted hydrazine Or substituted or unsubstituted An azole, or a pharmaceutically acceptable salt thereof. 一種醫藥組合物，其包含如請求項1至16中任一項之化合物，或其醫藥學上可接受之鹽。 A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof. 一種具有BACE1抑制活性之醫藥組合物，其包含如請求項1至16中任一項之化合物，或其醫藥學上可接受之鹽。 A pharmaceutical composition having a BACE1 inhibitory activity, which comprises a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof. 如請求項17或18之醫藥組合物，其用於治療或預防阿茲海默癡呆症、輕度認知障礙或前驅性阿茲海默氏病(prodromal Alzheimer's disease)，用於預防阿茲海默癡呆症、輕度認知障礙或前驅性阿茲海默氏病之進展，或用於預防無症狀患者之阿茲海默癡呆症風險之進展。 The pharmaceutical composition according to claim 17 or 18 for use in the treatment or prevention of Alzheimer's dementia, mild cognitive impairment or prodromal Alzheimer's disease for preventing Alzheimer's disease Advances in dementia, mild cognitive impairment, or prodromal Alzheimer's disease, or the risk of preventing Alzheimer's dementia in asymptomatic patients.
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